RU2509080C2 - Replaced dihydropyrazolones as inhibitors of hif-prolyl-4-hydroxylase - Google Patents

Abstract

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula

,

X means N or CH, R¹ means hydrogen or cyano, R² means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C₃-C₆-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

Description

The present application relates to new substituted derivatives of dihydropyrazolone, methods for their preparation, their use for the treatment and / or prevention of diseases, as well as their use for the manufacture of medicines for the treatment and / or prevention of diseases, in particular cardiovascular and hematological diseases, kidney diseases and to stimulate wound healing.

An insufficient supply of oxygen to the human body or its organs, which, due to the duration and / or scale, either disrupts the proper functioning of the body or its organs, or completely paralyzes their functions, is called hypoxia. Hypoxia can be caused by a decrease in oxygen in the inhaled air (for example, when staying high in the mountains), impaired external respiration (for example, as a result of impaired lung function or obstruction of the respiratory tract), a decrease in cardiac output (for example, with heart failure, with acute overload the right ventricle of the heart, with pulmonary embolism), a small oxygen transport capacity of the blood (for example, as a result of anemia (anemia) or intoxication, for example, carbon monoxide), can be localized in lack of blood supply due to vascular thrombosis (ischemic conditions, for example, heart, lower limbs or brain, diabetic macro- or microangiopathy) or caused by increased tissue oxygen demand (for example, as a result of intense muscular work or local inflammation) [Eder, Gedigk (Hrsg .), Allgemeine Pathologie und pathologische Anatomic, 33. Aufl., Springer Verlag, Berlin, 1990].

The human body is relatively able to adapt to situations of reduced oxygen supply in acute and chronic cases. In addition to the immediate response, in which the autonomic nervous mechanisms include an increase in cardiac output and temporary respiration, as well as local expansion of blood vessels, hypoxia leads to a change in the transcription of numerous genes. Moreover, the function of gene products compensates for the lack of oxygen. Thus, some glycolysis enzymes and glycolysis transporters 1 are intensely released, thereby increasing the release of anaerobic ATP and overcoming the lack of oxygen [Schmidt, Thews (Hrsg.), Physiologic des Menschen, 27. Aufl., Springer Verlag, Berlin, 1997; Loffler, Petrides (Hrsg.), Biochemie und Pathobiochemie, 7. Aufl., Springer Verlag, Berlin, 2003].

In addition, hypoxia leads to increased expression of the vascular endothelial cell growth factor, VEGF, as a result of which blood vessel formation (angiogenesis) is stimulated in tissues experiencing oxygen starvation. This improves the long-term blood supply of ischemic tissue. For various diseases associated with cardiac circulatory disorders and diseases associated with vascular thrombosis, such an oppositely directed regulatory mechanism is insufficiently implemented [review in: Simons und Ware, Therapeutic angio genesis in cardiovascular disease, Nat. Rev. Drug. Discov. 2 (11), 863-71 (2003)].

Further, with systematic hypoxia, the peptide hormone erythropoietin, which is formed mainly in interstitial kidney fibroplasts, is intensely released. This stimulates the formation of red blood cells in the bone marrow and, at the same time, the oxygen transport capacity of the blood. This effect was used and is used by record athletes in the so-called high-altitude training. A decrease in the oxygen transport capacity of the blood, for example, as a result of posthemorrhagic anemia, usually causes an increase in the formation of erythropoietins in the kidneys. In certain types of anemia, this regulatory mechanism can either be impaired, or the production of erythropoietins does not reach the specified parameter. So, for example, in patients suffering from renal failure, although erythropoietins are produced in the kidney parenchyma, they are in much smaller quantities relative to the oxygen transport capacity of the blood, resulting in so-called renal anemia. In particular, renal anemia, as well as anemia due to oncology and HIV infection, are usually treated with parenteral administration of recombinant human erythropoietins (rhEPO). Currently, for such an expensive treatment, there is no alternative therapy with an orally administered medicine [reviews: Eckardt, The potential of erythropoietin and related strategies to stimulate erythropoiesis, Curr. Opin. Investig. Drugs 2 (8), 1081-5 (2001); Bems, Should the target hemoglobin for patients with chronic kidney disease treated-with erythropoietic replacement therapy be changed ?, Semin. Dial 18 (1), 22-9 (2005)]. Recent studies confirm that erythroprotein, in addition to increasing erythropoiesis, also has a protective (anti-apoptotic) effect independent of it on tissues affected by hypoxia, in particular, on the heart and brain. Further, according to the results of recent studies, treatment with erythropoietin in patients with renal failure on average reduces the severity of the disease state [reviews in works:

Caiola und Cheng, Use of erythropoietin in heart failure management, Ann. Pharmacother 38 (12), 2145-9 (2004); Katz, Mechanisms and treatment of anemia in chronic heart failure. Congest. Heart Fail. 10 (5), 243-7 (2004)].

Together with the induced hypoxia of the genes described above, an increase in their expression during hypoxia is caused by the so-called hypoxia-induced transcription factor (HIF). As for the HIF factor, we are talking about a heterodimeric transcription factor, which consists of one alpha and one beta subunit. Three alpha isoforms of HIF factor are described, of which 1 alpha HIF and 2 alpha HIF are homologous subunits and are significant for hypoxia-induced gene expression. While the beta subunit (described by 2 isoforms), also called ARNT (aryl hydrocarbon receptor nuclear translocator: arylhydrocarboxylic nuclear translocator receptor), is constitutively isolated, the expression of the alpha subunit depends on the oxygen content in the blood. In normoxia, the alpha HIF protein is poly-ubiquitinated and then degraded into a protease. During hypoxia, this decomposition is inhibited, so that HIF alpha forms a dimeric compound with ARNT and can activate their target genes. In this case, the HIF dimer attaches to the so-called active elements of hypoxia (HRE) in the regulatory sequences of their target genes. HRE elements are defined by semantic sequence. Functional HREs have been found in the regulatory elements of numerous hypoxia-induced genes [reviews: Semenza, Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol. Med. 7 (8), 345-50 (2001);

Wenger und Gassmann, Oxygen (es) and the hypoxia-inducible factor-1: Biol. Chem. 378 (7), 609-16 (1997)].

The molecular mechanism underlying the regulation of HIF-alpha is explained by the work of several independent research groups. In general terms, this mechanism seems to be as follows: HIF alpha is hydroxylated, denoted as PHD or EGLN, a subclass of oxygen-dependent prolyl 4-hydroxylases into two specific prolyl residues (P402 and P564 of the human subunit 1 alpha HIF). Regarding HIF prolyl 4-hydroxylase, it is an iron dependent dioxigenase that converts oxoglutarate [Epstein et al., C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation, Cell 107 ( 1), 43-54 (2001); Bruick und McKnight, A conserved family of prolyl-4-hydroxylases that modify HIF, Science 294 (5545), 1337-40 (2001); Ivan et al., Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor, Proc. Natl. Acad. Sci. U.S.A. 99 (21), 13459-64 (2002)]. Enzymes were first duplicated in 2001 as prolyl hydroxylases [Aravind und Koonin, The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate-and iron-dependent dioxygenases, Genome Biol. 2 (3), research0007.1-0007.8, Epub 2001 Feb 19].

A pVHL tumor-inhibiting protein is attached to the polyhydroxylated alpha subunit of HIF, which together with elongin B and C forms the so-called VBC complex, which adapts the alpha subunit of HIF to the E3 ubiquitin ligase. Since prolyl-4-hydroxylation of the alpha HIF subunit and its subsequent decomposition is carried out depending on the intracellular oxygen concentration, HIF prolyl-4-hydroxylase is also called a cell oxygen sensor. Three isoforms of these enzymes have been identified: EGLN1 / PHD2, EGLN2 / PHD1 and EGLN3 / PHD3. Of these, two enzymes (EGLN2 / PHD1 and EGLN3 / PHD3) are induced by transcription even during hypoxia and may be responsible for the decrease in the level of HIF alpha observed in chronic hypoxia [see Schofield und Ratcliffe, Oxygen sensing by HIF hydroxylases, Nat. Rev. Mol. Cell. Biol. 5 (5), 343-54 (2004)].

Selective pharmacological inhibition of HIF prolyl 4-hydroxylases leads to an increase in the expression of HIF-dependent target genes and is therefore used to treat many diseases. In particular, with diseases of the cardiovascular system, an improvement in the course of the disease can be expected with the induction of new blood vessels, as well as with a change in the metabolism of ischemic organs from aerobic to anaerobic ATP secretion. Improving the vascularization of chronic wounds promotes the healing process, in particular, ulcers of Ulcera cruris and other chronic skin wounds that are difficult to heal. In certain forms of the disease, in particular in patients with renal anemia, the induction of autologous erythropoietin also presents a noteworthy therapeutic goal.

The HIF prolyl 4-hydroxylase inhibitors described to date in the scientific literature do not satisfy the requirements for the drug. In this case, we are talking either about competitive analogues of oxoglutarate (such as, for example, N-oxalyl glycine), which are very low efficient and therefore have not yet shown any action on in vivo samples in the sense of inducing HIF target genes. Either we are talking about iron-forming complexes (chelators) like desferroxamine, which act as non-specific inhibitors of iron-containing dioxygenases, and which, although they induce target genes, such as erythropoietin in vivo, suppress erythropoiesis due to the combination of available iron.

2-Heteroaryl-4-aryl-dihydropyrazolones with bactericidal and fungicidal effects are published in EP 165 448 and EP 212281. The use of 2-heteroaryl-4-aryl-dihydropyrazolones as lipoxygenase inhibitors for the treatment of respiratory diseases, diseases associated with cardiac disorders blood circulation, and inflammatory diseases are described in EP 183 159. 2,4-diphenyl-1,2-dihydropyrazolones with herbicidal activity are described in DE 2 651 008. The pharmacological properties of certain 2-pyridyl-dihydropyrazolones are reported in Helv. Chim. Acta 49 (1), 272-280 (1966). WO 96/12706, WO 00/51989 and WO 03/074550 describe compounds with a partial structure of dihydropyrazolones for the treatment of various diseases, and in WO 2006/101903 published bipyrazoles substituted with hydroxy or alkoxy groups for the treatment of neuropsychiatric diseases. Further, WO 03/051833 and WO 2004/089303 describe heteroaryl substituted pyrazole derivatives for treating pain and various diseases of the central nervous system. In WO 2006/114213, 2,4-dipyridyl-1,2-dihydropyrazolones were described as inhibitors of HGR-prolyl-4-hydroxylases.

On X-ray diffraction analysis of crystals of the compound 3-methyl-1- (pyridin-2-yl) -4- (1-pyridin-2-yl-3-methyl-1H-pyrazol-5-yl) -2H-3-pyrazolin-5 (1H) -one (another name: 5,5'-dimethyl-2,2'-dipyridin-2-yl-1 ', 2'-dihydro-2H, 3'H-3,4'-bipyrazole-3' -on) is reported in Acta Crystallogr., Section E: Structure Reports Online E57 (11), oll26-oll27 (2001) [Chem. Abstr. 2001: 796190]. The synthesis of certain derivatives of 3 ', 5-dimethyl-2-phenyl-1' - (1,3-thiazol-2-yl) -1H, 2H-3,4'-bipyrazole-5'-tins is described in Indian J. Heterocyclic Chem. 3. (1), 5-8 (1993) [Chem. Abstr. 1994: 323362]. The preparation and tautomerism of individual 4- (pyrazol-5-yl) -pyrazolin-5-ones derivatives is reported in J. Heterocyclic Chem. 27 (4), 865-870 (1990) [Chem. Abstr. 1991: 428557]. The therapeutic use of the compounds named in these publications has not yet been described. WO 2007/008541 discloses a compound 2-tert-butyl-1 '- [4- (4-chlorophenyl) -1,3-thiazol-2-yl] -3', 5-dimethyl-1'H, 2H- 3,4'-bipirazol-5'-ol as a test example.

The objective of the present invention is to provide new compounds that can be used to treat diseases, in particular cardiovascular and hematological diseases.

In the framework of the present invention describes compounds that act as specific inhibitors of HIF-prolyl-4-hydroxylases, and which due to their specific mechanism of action in vivo after parenteral or oral administration lead to the induction of HIF target genes, such as erythropoietin, and to they biological processes, such as erythropoiesis.

The subject of the invention are compounds of the formula

,

,

wherein

X is N or CH,

R ¹ means hydrogen or piano,

R ² means a saturated 4-7 membered heterocyclyl residue linked through a nitrogen atom,

moreover, the heterocyclyl residue may be substituted with one substituent selected from the group consisting of hydroxy, hydroxycarbonyl, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkylamino and C ₃ -C ₆ -puyualkyl, or wherein the heteropicl residue may be substituted 1-4 substituents fluorine, and their salts, their solvates and solvates of their salts.

Compounds according to the invention are compounds of formula (I) and their salts, solvates and solvates of salts, as well as compounds covered by formula (I), subsequently named as example (examples) of execution, and their salts, solvates and solvates of salts, if not salts, solvates and solvates of salts of both types covered by formula (I), subsequently named compounds.

The compounds according to the invention, depending on their structure, can exist in stereoisomeric forms (enantiomers, diastereomers). Therefore, the invention enantiomers or diastereomers and their corresponding mixtures are encompassed. From these mixtures of enantiomers and / or diastereomers, stereoisomeric homogeneous components can be isolated by known methods.

If the compounds according to the invention can be presented in tautomeric forms, the present invention covers all tautomeric forms.

As salts within the framework of the present invention, salts of the compounds of the invention that are not hazardous to physiology are preferred. Salts which are themselves unsuitable for pharmaceutical applications but which can be used, for example, to isolate or purify the compounds of the invention are also encompassed.

The physiologically non-hazardous salts of the compounds according to the invention include salts of mineral acids, carboxylic acids and sulfonic acids, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid , propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Non-hazardous physiological salts of the compounds of the invention also include salts of common bases, such as, for example, and mainly alkali metal salts (sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1-16 carbon atoms, such as, for example, and mainly ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine , arginine, lysine, ethylenediamine and N-methylpiperidine.

As solvates in the framework of the present invention are called such types of compounds according to the invention, which in the solid or liquid state form a complex by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination with water occurs. In the framework of the present invention, hydrates are preferred as solvates.

In addition, the present invention also encompasses prodrugs of the compounds of the invention. The term "prodrugs" includes compounds that themselves can be biologically active or inactive, but which in the body are converted into compounds according to the invention (for example, by a metabolic or hydrolytic route).

In the framework of the present invention, substituents have the following meaning, unless otherwise defined:

By itself, alkyl or “alkyl” in the alkylamino group means a linear or branched chain alkyl residue with 1 to 3 carbon atoms, for example, and preferably methyl, ethyl, n-propyl, isopropyl.

Alkylamino means an alkylamino residue with one or two (independently selected from each other) alkyl substituents, for example, and preferably means methylamine, ethylamino, n-propylamino, isopropylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl- N-methylamino, N-methyl-N-n-propylamino and N-isopropyl-N-n-propylamino. C ₁ -C ₃ -alkylamino means, for example, a monoalkylamino residue with 1-3 carbon atoms or a dialkylamino residue with 1-3 carbon atoms, respectively, in each alkyl substituent.

Cycloalkyl means a monocyclic group of cycloalkyl, usually with 3-6 carbon atoms, for example, and preferably means cycloalkyl called cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

A saturated 4-7 membered heterodicyclic residue linked through a nitrogen atom means a monocyclic, saturated, heterocyclic residue with 4-7 ring atoms, containing the nitrogen atom through which it is bound, and not more than 2, mainly not more than one additional heteroatom and / or hetero groups from the series N, O, S, SO, SO ₂ , moreover, the nitrogen atom can form nitric oxide. Preferred are 4-7 membered, monocyclic saturated heterocyclyl residues with a maximum of one additional heteroatom from the series O, N and S, for example, and preferably acetidin-1-yl, pyrrolin-1-yl, piperidin-1-yl, morpholin-4 -yl, thiomorpholin-4-yl, piperazin-1-yl, 1,2-oxazinan-2-yl, 1,4-oxazepan-4-yl, 1,4-thiazepan-4-yl.

Preferred compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or cyano,

R ² means a saturated 4-7 membered heterocyclyl residue linked through a nitrogen atom,

moreover, the heterocyclyl residue is substituted by 1-4 substituents fluorine, or R ² means piperazin-1-yl,

wherein piperazin-1-yl is substituted with one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl, or R ² is acetidin-1-yl,

wherein acetidin-1-yl is substituted with one substituent selected from the group consisting of hydroxycarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkylamino and C ₃ -C ₆ cycloalkyl, or

R ² means 1,2-oxazinan-2-yl or 1,4-oxazepan-4-yl,

and their salts, their solvates and solvates of their salts.

Preferred compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or piano,

R ² means acetidin-1-yl, pyrrolin-1-yl or piperidin-1-yl,

wherein acetidin-1-yl, pyrrolin-1-yl and piperidin-1-yl are substituted

1-4 fluorine substituents,

or

R ² means piperazin-1-yl,

wherein piperazin-1-yl in the 4th position is substituted with one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl,

or

R ² means acetidin-1-yl,

moreover, acetidin-1-yl in the 3rd position is substituted by one substituent,

selected from the group consisting of hydroxycarbonyl, methyl, and

dimethylamino

or

R ² means 1,2-oxazinan-2-yl or 1,4-oxazepan-4-yl,

and their salts, their solvates and solvates of their salts.

Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or cyano,

R ² means a saturated 4-7 membered heterocyclyl residue,

bonded through a nitrogen atom,

moreover, the heterocyclyl residue is substituted by 1-4 substituents fluorine, and their salts, their solvates and solvates of their salts.

Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or cyano,

R ² means acetidin-1-yl, pyrrolin-1-yl or piperidin-1-yl,

wherein acetidin-1-yl, pyrrolin-1-yl and piperidin-1-yl are substituted

1-4 fluorine substituents,

and their salts, their solvates and solvates of their salts.

Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or cyano,

R ² means acetidin-1-yl, pyrrolin-1-yl or piperidin-1-yl,

moreover, acetidin-1-yl, pyrrolin-1-yl and piperidin-1-yl are substituted by 2 fluorine substituents, and these substituents are attached to the same carbon atom,

and their salts, their solvates and solvates of their salts. Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or piano,

R ² means piperazin-1-yl,

wherein piperazin-1-yl is substituted with one substituent selected from

a group consisting of C ₃ -C ₆ cycloalkyl, and their salts, their solvates and solvates of their salts.

Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or cyano,

R ² means piperazin-1-yl,

and piperazin-1-yl in the 4th position is substituted by one substituent,

selected from the group consisting of C ₃ -C ₆ cycloalkyl, and their salts, their solvates and solvates of their salts. Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or piano,

R ² means acetidin-1-yl,

wherein acetidin-1-yl is substituted with one substituent selected from the group consisting of hydroxycarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkylamino and C ₃ -C ₆ cycloalkyl,

and their salts, their solvates and solvates of their salts.

Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or cyano,

R ² means acetidin-1-yl,

wherein acetidin-1-yl is substituted with one substituent selected from the group consisting of hydroxycarbonyl, methyl and dimethylamino,

and their salts, their solvates and solvates of their salts.

Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or piano,

R ² means apetidin-1-yl,

moreover, apetidin-1-yl in the 3rd position is substituted by one substituent selected from the group consisting of gadroxycarbonyl, methyl and dimethylamino,

and their salts, their solvates and solvates of their salts.

Compounds of formula (I) in which

X is N or CH,

R ¹ means hydrogen or piano,

R ² is 1,2-oxazinan-2-yl or 1,4-oxazepan-4-yl.

Also preferred are compounds of formula (I) in which X is N.

Also preferred are compounds of formula (I) in which R ¹ is hydrogen.

Compounds of formula (I) in which R ¹ is piano are also preferred.

Also preferred are compounds of formula (I) in which R ² is 4-cyclobutyl-piperazin-1-yl.

Compounds of formula (I) in which

X is N or CH,

R ¹ means piano

R ² means a saturated 4-7 membered heterocyclyl residue linked through a nitrogen atom,

wherein the heterocyclyl residue is substituted with one substituent selected from the group consisting of hydroxy, hydroxycarbonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkylamino and C ₃ -C ₆ cycloalkyl, or

moreover, the heterocyclyl residue is substituted by 1-4 substituents fluorine,

and their salts, their solvates and solvates of their salts.

Specified in particular definitions of residues in the respective and preferred combinations of residues are optionally replaced also by definitions of residues of other combinations, regardless of the respective indicated combinations of residues.

Most preferred are combinations of two or more of the above-mentioned areas of preference.

According to the invention, the 1,2-dihydropyrazol-3-one derivatives of the formula (I) can also be represented in the tautomerism form of 1H-pyrazol-5-ol (I ') (see Scheme 1 below); both tautomeric forms are encompassed by the present invention.

Scheme 1

Further, the subject of the invention is a method for producing compounds of formula (I), or their salts, their solvates or solvates of their salts, and according to the method

[A] compounds of the formula

,

,

in which R ¹ has the above meaning, and

Z ¹ means methyl or ethyl,

in an inert solvent, if necessary, in the presence of one of the acids with a compound of the formula

,

,

in which R ² has the above meaning,

converted to compounds of the formula

in which Z ¹ , R ¹ and R ² have the above meanings,

which, even under these reaction conditions or in the subsequent reaction, are converted into cyclic compounds of the formula (I) under the influence of a base,

and the compounds of formula (I), if necessary, are converted into their salts, their solvates or solvates of their salts, using appropriate (i) solvents and / or (ii) bases or acids,

or

[B] compounds of the formula

in which Z ¹ and R ¹ have the above meanings,

with a compound of the formula

wherein

Z ² means methyl or ethyl,

condensed into compounds of the formula

in which Z ¹ and R ¹ have the above meanings,

and then, in the presence of one of the acids with a compound of formula (III), it is converted into compounds of formula (IV), which are already converted to cyclic compounds of formula (I) under these reaction conditions or in the subsequent reaction under the action of a base,

and the compounds of formula (I), if necessary, are converted into their salts, their solvates or solvates of their salts, using appropriate (i) solvents and / or (ii) bases or acids,

or

[C] a compound of the formula

in water, as a solvent, the Eintopf method (“one tube”) is first reacted with compounds of the formula

which R ² has the above meaning,

and then with compounds of formula (VII) with conversion to compounds of formula (I),

and the compounds of formula (I), if necessary, are converted into their salts, their solvates or solvates of their salts with the appropriate (i) solvents and / or (ii) bases or acids.

The free base of salts can be obtained by the reaction of the exchange of salts of compounds or solvates of salts of compounds with a base.

Suitable bases are alkali metal hydroxides, such as sodium or potassium hydroxide, alkali or alkaline earth metal carbonates, such as sodium, potassium, calcium or cesium carbonate, or

aqueous ammonia.

In an alternative method, the free base of the salts can be obtained, for example, by chromatography on a reverse phase column with an acetonitrile-water gradient by adding a base, in particular using a Phenomenex Luna C 18 (2) RP18 column and diethylamine as the base.

A further subject of the invention is a process for the preparation of compounds of formula (I) and their solvates, in which salts of compounds or solvates of salts of compounds are exchanged into the compounds by an exchange reaction with a base or by chromatography upon addition of a base.

Further, the compounds according to the invention can be obtained, under known conditions, by conversion of the functional groups of the individual substituents, in particular, indicated by the symbols R ¹ and R ² , starting from the compounds of formula (I) obtained by the methods described above. These transformations are carried out by standard methods known to those skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution, oxidation, reduction, hydrogenation, transition metal catalyzed coupling reactions, alkylation, acylation, amination, ester formation, ester cleavage, ether formation ether, ether cleavage, formation of carbonamides, sulfamides, carbamates and urea, as well as the introduction and removal of temporary end groups.

As inert solvents for the process steps (II) + (III) → (IV), (VII) + (III) → (IV) and (IV) → (I), ethers such as diethyl ether, methyl are particularly suitable tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, or alcohols like methanol, ethanol, n-propanol, iso-propanol, n-butanol and tert-butanol, or water, or solvent mixtures, or a mixture of solvent with water. The use of methanol, ethanol, tetrahydrofuran or water is preferred.

The process step (V) + (VI) → (VII) is preferably carried out in dimethylformamide as a solvent, or in the presence of an excess of compound (VI) without an additional solvent. In some cases, the reaction can also be performed predominantly under microwave irradiation. The exchange reaction is carried out in the General case at a temperature of from + 20 ° C to + 150 ° C, preferably at a temperature of from + 80 ° C to 120 ° C [see also J.P. Bazureau et aL, Synthesis 1998, 967; ibid. 2001 (4), 581].

In some cases, the process steps (II) + (III) → (IV) and (VII) + (III) → (IV) can be carried out predominantly with the addition of acid. Conventional inorganic or organic acids are suitable for this, such as, for example, hydrogen chloride, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or camphor-10-sulfonic acid. The use of acetic acids, in particular trifluoroacetic acid or p-toluenesulfonic acid, is preferred.

The exchange reaction (II) + (III) → (IV) is generally carried out at a temperature from 0 ° C to + 100 ° C, preferably from + 10 ° C to + 50 ° C. Reaction (VII) + (III) → (IV) is generally carried out at a temperature of from + 20 ° C to + 120 ° C, preferably from + 50 ° C to + 100 ° C.

The sequence of the method (II) + (III) → (IV) → (I) and (VIII) + (III) → (IV) → (I) can be performed in two stages or in the same way as the “Eintopf” reaction without highlighting the intermediate stage ( Iv). For the latter option, in particular, the conversion of components upon microwave irradiation is suitable; the reaction is generally carried out at a temperature of from + 50 ° C to + 200 ° C, preferably at a temperature of from + 100 ° C to + 180 ° C.

In part, the closure of the cycle, approaching compound (I), begins already upon receipt of compound (IV); cyclization can be completed by treating the in situ reaction mixture with any base.

Conventional inorganic or organic bases are suitable as a base for such an isolated cyclization step (IV) → (I). These include, in particular, alkali metal hydroxides, such as sodium or potassium hydroxide, alkali or alkaline earth metal carbonates, such as sodium, potassium, calcium or cesium carbonate, alkali metal alkoxides such as sodium or potassium methanolate, sodium or potassium ethanolate, or sodium or potassium tert-butylate, or alkali metal hydrides like sodium hydride. The use of sodium methanolate or ethanolate is preferred.

The base-induced exchange reaction (IV) → (I) is generally carried out at a temperature of from 0 ° C to + 60 ° C, preferably from 0 ° C to + 30 ° C.

The exchange reaction (VIII) + (IX) + (VII) → (I) is carried out using 1.1-2.0 equivalents of the compounds of formula (IX) relative to 1 equivalent of the compounds of formula (VIII), if necessary, in the presence of 1, 1 to 2.0 equivalents of base. An exchange reaction is preferred with 1.1-1.5 equivalents of the compound of formula (IX).

Conventional inorganic or organic bases are suitable as bases for the exchange reaction (VIII) + (IX) (+ (VIII) → (I). These include, in particular, alkali metal hydroxides, such as sodium or potassium hydroxide, or amine bases, such as N-ethyl-N- (propan-2-yl) propan-2-amine, N-ethyl-N- (propan-2-yl) propan-2-amine is preferred.

The exchange reaction (VIII) + (IX) + (VII) → (I) is carried out in the General case at a temperature from + 20 ° C to + 100 ° C, preferably at a temperature from + 70 ° C to + 100 ° C.

All stages of the method can be performed at normal, elevated or reduced pressure (for example, from 0.5 to 5 bar). As a rule, work is carried out at normal pressure.

Compounds of formula (II) can be prepared by methods described in the literature for C-acylation of sulfonic acid esters from compounds of formula (V). Compounds of formulas (III), (V), (VI), (VIII) and (IX) are commercially available, known from the literature, or can be obtained by analogy with the methods described in the literature.

Obtaining compounds according to the invention is clearly shown in the following reaction scheme 2:

Scheme 2

[a): dimethylformamide, 16 hours, + 100 ° C; b): ethanol, trifluoroacetic acid, + 78 ° C; c): NaOEt, ethanol, 1 hour, room temperature].

The compounds of the invention show an unexpectedly complete pharmacological spectrum of action.

Therefore, they are suitable for use as medicines for the treatment and / or prevention of diseases in humans and animals.

The compounds of the invention differ as specific inhibitors of H1P-prolyl-4-hydroxylase.

The compounds according to the invention, due to their pharmacological properties, can be used for the treatment and / or prevention of diseases of the cardiovascular system, in particular heart failure, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, essential, pulmonary and malignant hypertension, as well as peripheral obliterating disease

The compounds according to the invention are also suitable for the treatment and / or prophylaxis of hematopoiesis, such as idiopathic anemia, renal anemia and anemia accompanied by cancer (in particular chemotherapy anemia), infection (in particular HIV infection ) or other inflammatory diseases, such as rheumatoid arthritis. In addition, the compounds of the invention are suitable for the supportive treatment of anemia due to blood loss, iron deficiency anemia, vitamin deficiency anemia (e.g., due to a lack of vitamin B-12 or a lack of folic acid), hypoplastic and aplastic anemia, hemolytic anemia, or for the supportive treatment of anemia impaired absorption of iron (iron-refractory anemia) or anemia due to other endocrine disorders (e.g. hypothyroidism).

Further, the compounds are suitable for increasing hematocrit in order to obtain blood to replenish their own blood before surgery.

In addition, the compounds according to the invention can be used for the treatment and / or prophylaxis of ischemic conditions caused by operations and their consequences after surgery, in particular, after heart operations using an artificial heart and lungs (for example, bypass surgery, implantation of heart valves), operations on carotid artery, operations on the aorta and operations with instrumental opening or penetration of the roof of the skull. Further, the compounds are suitable for general treatment and / or prophylaxis during surgical interventions in order to accelerate wound healing and shorten recovery time.

In addition, the compounds are suitable for the treatment and prophylaxis of the effects of acute and protracted ischemic conditions of the brain (for example, apoplexy stroke, birth asphyxia).

Further, the compounds can be used for the treatment and / or prevention of cancer and for the treatment and / or prevention of health impairment occurring during the treatment of cancer, in particular after treatment with cytotoxic drugs, antibiotics and radiation.

The compounds are also suitable for the treatment and / or prophylaxis of rheumatic diseases and other forms of diseases classified as autoimmune diseases and, in particular, for the treatment and / or prophylaxis of ill health occurring during the medical treatment of such diseases.

In addition, the compounds of the invention can be used to treat and / or prevent eye diseases (e.g., glaucoma), brain (e.g., Parkinson's disease, Alzheimer's disease, dementia, chronic pain), chronic kidney disease, kidney failure and acute kidney failure, and also to stimulate wound healing.

Furthermore, the compounds of the invention are suitable for the treatment and / or prophylaxis of general physical weakness, which is often found at a very advanced age until exhaustion.

Further, the compounds are suitable for the treatment and / or prevention of sexual dysfunction.

In addition, the compounds are suitable for the treatment and / or prevention of diabetes mellitus and its complications, such as diabetic macro- and microangiopathy, diabetic nephropathy and neuropathy.

Further, the compounds of the invention are suitable for the treatment and / or prophylaxis of fibrotic diseases, for example, heart, lungs and liver.

In particular, the compounds of the invention are also suitable for the prophylaxis and treatment of retinopathy of premature babies (Retinopathia praematurorum).

The next subject of the present invention is the use of the compounds according to the invention for the treatment and / or prevention of diseases, in particular, the above diseases.

The next subject of the present invention is the use of the compounds according to the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

The next subject of the present invention is a method for the treatment and / or prevention of diseases, in particular, the above diseases, using an effective amount of at least one of the compounds according to the invention.

Compounds according to the invention can be used alone or, if necessary, in combination with other biologically active substances. The next subject of the present invention are medicines containing at least one of the compounds according to the invention and one or more active substances, in particular for the treatment and / or prevention of the above diseases. Suitable combinations of active substances, for example, and mainly, may include the following: ACE inhibitors, angiotensin II receptor antagonists, beta-receptor blockers, calcium antagonists, phosphodiesterase (PDE) inhibitors, mineralocorticoid receptor antagonists, diuretics, aspirin, additives iron, vitamin B 12 and folic acid supplements, statins, digitalis derivatives (digoxin), oncological chemotherapeutic drugs and antibiotics.

In a preferred embodiment of the invention, the compounds of the invention are produced in combination with any ACE inhibitor, such as, for example, and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds of the invention are produced in combination with any angiotensin II antagonist, such as, for example, and primarily, losartan, candesartan, valzartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according to the invention are produced in combination with any beta-receptor blocker, such as, for example, and mainly, propranolol, atenolol, timolol, pirdolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol , sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, cartolol, esmolol, labetalol, carvedilol, adaptrolol, landiolol, nebivolol, epanolol or butcindolol.

In a preferred embodiment of the invention, the compounds of the invention are produced in combination with a calcium antagonist, such as, for example, and preferably nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds of the invention are produced in combination with any phosphodiesterase inhibitor (PDE), such as, for example, and predominantly, milrinone, amrinone, pimopendan, cilostazol, sildenafil, vardenafil or tadalafil.

In a preferred embodiment of the invention, the compounds of the invention are produced in combination with an antagonist of mineralocorticoid receptors, such as, for example, and predominantly spironolactone, eplerenone, canrenone or potassium canrenoate.

In a preferred embodiment of the invention, the compounds according to the invention are produced in combination with any diuretic, such as, for example, and mainly, furozemide, bumetanide, torzemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methiclotiazide, poithiazide, trichloromethiazide, inlortortazidone, chlorodiazide, chlorodiazide, , quinetasone, acetazolamide, dichlorophenamide, metazolamide, glycerin, isosorbide, mannitol, amiloride or triamteren.

In a preferred embodiment of the invention, the compounds according to the invention are produced in combination with any HMG-CoA reductase inhibitor from the class of statins, such as, and mainly, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are produced in combination with any oncological chemotherapeutic agent, for example, and mainly from the group of platinum complexes, such as, for example, cisplatin and carboplatin, from the group of alkylants, such as, for example, cyclophosphamide and chlorambucil, from groups of antimetabolites, such as 5-fluorouracil and methotrexate, from the group of topoisomerase inhibitors, such as etoposide and camothecine, from the group of antibiotics, such as doxorobicin and daunorubits n, or grauppy kinase inhibitors, such as, e.g., sorafenib and sunitinib.

In a preferred embodiment of the invention, the compounds according to the invention are produced in combination with any antibiotic, for example, and preferably from the group of penicillins, cephalosporins or quinolones, such as, for example, ciprofloxacin and moxifloxacin.

The next object of the present invention are medicines containing at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmacologically acceptable excipients, as well as their use for the previously mentioned purposes.

The compounds of the invention may act systemically or locally. For this purpose, they can be taken in an appropriate way, such as orally, parenterally, pulmonally, nasally, under the tongue, on the tongue, buccally, rectally, dermally, transdermally, conjunctively, through the ears or as an implant and stent.

For these routes of administration, the compounds of the invention may be formulated in appropriate forms of use.

Oral administration is suitable for use according to the state of the art, quickly and / or in a modified form, dispensing compounds according to the invention, which contain compounds according to the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (coated tablets or without coating, for example, with gastric juice resistant coatings, delayed or insoluble coatings that control the release of the compound of the invention), rapidly disintegrating in the oral cavity, tablets or wafers / wafers, wafers / lyophilisates, capsules (for example, hard or soft gelatin capsules), dragees, granules, granules, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass the absorption stage (e.g., intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with the inclusion of absorption (e.g., intramuscularly, subcutaneously, intradermally, percutaneously or intraperitoneally). Suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration, for example, inhalation dosage forms (inter alia, powder inhalers, nebulizers), drops, solutions or nasal sprays, tablets taken on the tongue, under the tongue or cheek, plates / cachets or capsules, suppositories, are suitable. ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, chatterboxes), fat-soluble suspensions, ointments, creams acting through the skin of the system (for example, patches), milk, pastes, foams, powders, implants and stents.

Oral or parenteral administration is preferred, in particular oral and intravenous administration.

Compounds according to the invention can be converted to these forms of use. This can be carried out in a known manner using inert, non-toxic, accepted in pharmacology excipients. These excipients include, but are not limited to, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol) emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxy sorbitan oleate), binders (e.g. polyvinylpyrrole) artificial and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, such as ascorbic acid), dyes (e.g. inorganic pigments, such as oxide iron) and substances that improve the taste and / or smell.

To achieve a tangible result with parenteral administration, amounts should be prescribed, in the General case, from 0.001 to 1 mg / kg, mainly from 0.01 to 0.5 mg / kg of body weight. When taken orally, the dosage is 0.01-100 mg / kg, preferably 0.01-20 mg / kg, and particularly preferably 0.1-1 mg / kg body weight.

However, in some cases, one should deviate from the indicated amounts, namely, depending on the body weight, route of administration, individual tolerance of the active substance, type of preparation, and time or interval of administration. So, in some cases, the dosage may be sufficient in smaller quantities than the indicated minimum doses, while in other cases, the upper limits must be exceeded. In the case of the appointment of an increased dose, it is recommended to divide it into several doses per day.

The following examples of execution explain the invention. The invention is not limited to the examples given.

The data indicated as a percentage in the following tests and examples, unless otherwise indicated, are weight percent; shares are parts by weight. The ratios of solvents, diluents and concentration data for liquid / liquid solutions refer to the respective volumes.

A. Examples

Abbreviations:

aq. Water solution cat. Catalytic d Day (s) DCI Direct chemical ionization (for MS) DMF Dimethylformamide Dmso Dimethyl sulfoxide theor. prob. Relative to the theoretically possible, (output) Ei Electron impact ionization (for MS) ESI Electrospray ionization (for MS) Et Ethyl Gc-ms Gas chromatography combined with mass spectroscopy h Hour (hours) HPLC High pressure liquid chromatography, high resolution liquid chromatography conc. Concentrated LC-MS Liquid chromatography combined with mass spectroscopy met. Method min Minute (minutes) Ms Mass spectroscopy NMR Nuclear Resonance Spectroscopy (NMR) R _t Retention Time (with HPLC) Kt Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran

LC-MS methods. GC-MS and HPLC:

Method 1 (LC-MS): tool: Micromass Platfonn LCZ with HPLC Agilent Serie 1100; column: Thermo Hypersil GOLD 3µ, 20 mm × 4 mm; eluent A: 1 l of water + 0.5 ml of 50% acetic acid; eluent B: 1 l of acetonitrile + 0.5 ml of 50% acetic acid; gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; oven: 50 ° C; flow: 0.8 ml / min; UV detection: 210 nm.

Method 2 (LC-MS): instrument type MS: Micromass ZQ; HPLC device type:

Waters Alliance 2795; column: Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm × 4 mm; eluent A: 1 l of water + 0.5 ml of 50% acetic acid; eluent B: 1 l of acetonitrile + 0.5 ml of 50% acetic acid; gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; oven: 50 ° C; UV detection: 210 nm.

Method 3 (LC-MS): instrument type MS: Micromass ZQ; HPLC device type:

Waters Alliance 2795; column: Phenomenex Synergi 2.5µ. MAX-RP 100A Mercury 20 mm × 4 mm; eluent A: 1 l of water + 0.5 ml of 50% acetic acid; eluent B: 1 l of acetonitrile +0.5 ml of 50% acetic acid; gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; flow: 2 ml / min; oven: 50 ° C; UV detection: 210 nm.

Method 4 (LC-MS): Instrument: Micromass Quattro Micro MS with HPLC Agilent Serie 1100; column: Thermo Hypersil GOLD 3µ 20 mm × 4 mm; eluent A: 1 l of water + 0.5 ml of 50% acetic acid; eluent B: 1 l of acetonitrile + 0.5 ml of 50% acetic acid; gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow 2.5 ml / min) → 5.00 min 100% A; oven: 50 ° C; flow: 2 ml / min; UV detection: 210 nm.

Method 5 (LC-MS): Tool: Micromass QuattroPremier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9µ 50 mm × 1 mm; eluent A: 1 l of water +0.5 ml of 50% acetic acid; eluent B: 1 l of acetonitrile +0.5 ml of 50% acetic acid; gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; flow: 0.33 ml / min; oven: 50 ° C; UV detection: 210 nm.

Method 6 (HPLC): Tool: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; eluent A: 5 ml of perchloric acid (70%) / liter of water, eluent B: acetonitrile; gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% V; flow: 0.75 ml / min; column temperature: 30 ° C; UV detection: 210 nm.

Method 7 (GC-MS): Tool: Micromass GCT, GC6890; column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; constant flow with helium: 0.88 ml / min; oven: 70 ° C; inlet temperature: 250 ° C; gradient: 70 ° C, 30 ° C / min → 310 ° C (maintained for 3 minutes).

Method 8 (preparative HPLC): column: Kromasil 100 C 18 5 μm, 250 mm × 20 mm; eluent A: Milli-Q water, eluent B: aqueous 0.1% trifluoroacetic acid, eluent C: acetonitrile; gradient: 0.0 min 76% A, 5% B, 19% C → 15 min 4% A, 95% B, 1% C → 15.1 min 76% A, 5% B, 19% C → 20 min 76% A, 5% B, 19% C; oven: 40 ° C; flow: 25 ml / min; UV detection: 210 nm.

Method 9 (preparative HPLC): column: Sunfire C 18 5 μm, 19 mm × 150 mm; eluent A: aqueous 0.2% trifluoroacetic acid; eluent B: acetonitrile; gradient: 0.0 min 95% A → 8 min 50% A → 8.01 min 95% A → 12 min 95% A; CT

flow: 25 ml / min; UV detection: 210 nm.

Method 10 (preparative HPLC): column: Sunfire C 18 5 μm, 19 mm × 150 mm; eluent A: aqueous 0.2% trifluoroacetic acid; eluent B: acetonitrile; 0 min 90% A → 13 min 90% A; oven: 40 ° C; flow: 25 ml / min; UV detection: 210 nm.

Method 11 (preparative HPLC): column: XBridge C 18 5 μm, 19 mm × 150 mm; eluent A: aqueous 0.2% formic acid; eluent B: acetonitrile; 0 min 75% A → 6 min 75% A; CT flow: 25 ml / min; UV detection: 210 nm.

Method 12 (preparative HPLC): column: XBridge C 18 5 μm, 19 mm × 150 mm; eluent A: aqueous 0.2% formic acid; eluent B: acetonitrile; 0 min 93% A → 4 min 93% A; CT flow: 25 ml / min; UV detection: 210 nm.

Method 13 (preparative HPLC): column: XBridge C 18 5 μm, 19 mm × 150 mm; eluent A: aqueous 0.2% trifluoroacetic acid, eluent B: acetonitrile; 0 min 90% A → 12 min 90% A; oven: 40 ° C; flow: 25 ml / min; UV detection: 210 nm.

Source compounds

Example 1A

(4-cyano-1H-imidazol-1-yl) ethyl acetate

3.3 g (35.3 mmol) of 1H-imidazole-4-carbonitrile [Matthews et al., J. Org. Chem. 1986, 51, 3228-3231] is added in 13.2 ml (11.5 g, 35.3 mmol) of a 21% solution of sodium ethoxide in ethanol, and 4.3 ml (6.5 g, 38.9 mmol) are added. bromoethyl acetate. The reaction mixture was stirred for 16 hours at room temperature. For processing, the precipitated solid is filtered off, the filter cake is washed with ethanol, and the filtrate is concentrated in vacuo. The residue was diluted with diisopropyl ether, filtered again, the filtrate was again concentrated in a rotary evaporator, and the residue was dried in vacuo. Yield: 3.8 g (60% of theory. Prob.).

LC-MS (method I): R _t = 1.17 min; MS (ESIpos): m / z = 180 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.12 (s, 1H), 7.88 (s, 1H), 5.06 (s, 2H), 4.18 (q, 2H), 1.22 (t, 3H) .

Example 2A

2- (1 H-1,2,3-triazole-1-yl) ethyl acetate

129.2 g (5.6 mol) of sodium are slowly added to 4.0 liters of ethanol. Then, 400.0 g (5.6 mol) of 1,2,3-1H-triazole are added and 623 ml (938.2 g, 5.6 mol) of bromoethyl acetate are added at an internal temperature of 20-25 ° C. The mixture is stirred for 48 hours. at room temperature. The precipitated solid is filtered off, ethanol is removed in vacuo and filtered again. The residue was diluted with ethyl acetate, filtered, concentrated again in vacuo and purified by distillation in a 30 cm column. The product is obtained at a bath temperature of 140 ° C, a top temperature of 60-115 ° C and a pressure of 1 mbar. Yield :: 440.0 g (50% of theory. Prob.).

HPLC (method b): R _t = 1.58 min;

LC-MS (method I): R _t = 0.71 min; MS (ESIpos): m / z = 156 [M + H] ⁺ .

Example 3A

1H-Imidazol-1-yl-ethyl acetate

118.2 g (5.1 mol) of sodium are slowly added to 2.5 liters of ethanol. Then 350.0 g (5.1 mol) of imidazole are added and 570 ml (858.6 g, 5.1 mol) of bromoethyl acetate are added at an internal temperature of 20-25 ° C. The mixture was stirred for 24 hours at room temperature. The precipitated solid is filtered off, ethanol is removed in vacuo and filtered again. The residue was purified by silica gel column chromatography (solvent: ethyl acetate). Yield: 639.0 g (81% of theory. Prob.).

GC-MS (method 7): R _t = 4.55 min; MS (ESIpos): m / z = 155 [M + H] ⁺

Example 4A

(4-Cyano-1H-1,2,3-triazol-1-yl) ethyl acetate

4.1 g (31.9 mmol) of acididoacetate and 2.8 g (31.9 mmol) of 2-chloroacrylic acid nitrile are stirred in 32 ml of water for 16 hours at a bath temperature of 80 ° C. After cooling to room temperature, the solution was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with 50 ml of ethanol and 10 drops of concentrated sulfuric acid, and the mixture was stirred for 16 hours at reflux. For processing, the reaction mixture was concentrated in vacuo, the residue was diluted with ethyl acetate, the suspension was washed with a semi-concentrated sodium hydrogen carbonate solution, and the organic phase was dried over sodium sulfate. The solvent was completely removed in a rotary evaporator, and the residue was dried in vacuo. Yield: 1.5 g (25% of theory. Prob.).

LC-MS (method 3): R _t = 0.96 min; MS (ESIpos): m / z = 181 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSOO: 5 - 9.06 (s, 1H), 5.57 (s, 2H), 4.19 (q, 2H), 1.22 (t, 3H).

Example 5A

3- (N, N-Dimethylamino) -2- (1H-imidazol-1-yl) acrylic acid ethyl ester

38.0 g (244.9 mmol) of the compound of Example B were stirred in 126 ml (108.1 g, 734.7 mmol) of N, N-dimethylformamide-diethylacetal for 16 hours at a bath temperature of 90 ° C. After cooling, the mixture is concentrated in vacuo, stirred with diisopropyl ether, the solid is filtered off, then washed with diisopropyl ether. Yield: 49.0 g (95% theory. Prob.).

LC-MS (method 2): R _t = 2.42 min; MS (ESIpos): m / z = 211 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.52 (s, 1H), 7.49 (s, 1H), 7.05 (s, 1H), 6.91 (s, 1H), 4.02 (q, 2H) 2.63 (br. S, 6H); 1.12 (t, 3H).

Example 6A

3- (N-dimethylamino) -2- (4-cyano-1H-imidazol-1-yl) acrylic acid ethyl ester

3.8 g (21.4 mmol) of the compound of Example 1A and 7.4 ml (6.3 g, 42.8 mmol) of N, N-dimethylformamide-diethylacetal were stirred for 16 hours at a bath temperature of 100 ° C. For processing, the cooled reaction solution is concentrated in a rotary evaporator, and the residue is dried in vacuum. Yield: 5.0 g (73% purity, 73% theory. Prob.).

LC-MS (method I): R _t = 2.69 min; MS (ESIpos): m / z = 235 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.13 (s. 1H), 7.85 (s, 1H), 7.58 (s, 1H), 4.03 (q, 2H), 2.69 (br. S, 6H), 1.12 (t, 3H).

Example 7A

3- (Dimethylamino) -2- (4-cyano-1H-1,2,3-triazol-1-yl) acrylic acid ethyl ester

1.3 g (7.5 mmol) of the compound of Example 4A and 1.4 ml (1.2 g, 8.2 mmol) of N, N-dimethylformamide-diethylacetal were stirred for 16 hours at a bath temperature of 100 ° C. For processing, chilled the reaction solution is concentrated in a rotary evaporator, and the residue is dried in vacuum. Yield: 1.5 g (86% of theory. Prob.).

LC-MS (method 4): R _t = 1.55 min; MS (ESIpos): m / z = 236 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.14 (s, 1H), 7.75 (s, 1H), 4.04 (q, 2H), 3.15 (br.s, 3H), 2.18 (br. s, 3H), 1.13 (t, 3h).

Example 8A

3- (Dimethylamino) -2- (1H-1,2,3-triazol-1-yl) acrylic acid ethyl ester

20.0 g (128.9 mmol) of the compound of Example 2A was mixed with 44.2 ml (38.0 g, 257.8 mmol) of N, dimethylformamide-diethylacetal, and the mixture was stirred for 16 hours at 100 ° C. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was stirred in diethyl ether, filtered and washed with diethyl ether. Yield: 18.0 g (67% of theory. Prob.). LC-MS (method 4): R _t ⁼ 1.20 min; MS (ESIpos): m / z = 211 [M + H] ⁺ .

¹ H-NMR (400 MHz. DMSO-d ₆ ): δ = 8.10 (d, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 4.03 (q, 2H), 3.06 (br. S, 3H), 2.10 (br. S, 3H), 1.12 (t, 3H).

Example 9A

4- (4-Cyclobutylpiperazin-1-yl) -6-hydrazinopyrimidine

Step a): 4-Chloro-6- (4-cyclobugylpiperazin-1-yl) pyrimidine

1.8 g (8.4 mmol) of 1-cyclobutylpiperazine dihydrochloride (Zaragoza et al., J. Med. Chem. 2004, 47, 2833) are added to 18 ml of water and diluted with 2.9 ml (2.1 g, 16, 9 mmol) N-ethyl-N- (propan-2-yl) propan-2-amine. The mixture was stirred for 30 minutes at room temperature, and 1.3 g (8.4 mmol) of 4,6-dichloropyrimidine was added to it. The reaction mixture was stirred for 1 hour at 115 ° C, cooled to room temperature, diluted with 25 ml of ethyl acetate and extracted with a saturated aqueous solution of sodium bicarbonate. The organic phase is separated, dried over sodium sulfate, filtered and concentrated in vacuo. The starting material was purified by silica gel column chromatography (solvent: dichloromethane / methanol 100/3). Yield: 1.9 g (89% of theory. Prob.)

HPLC (method 6): R _t = 2.79 min; MS (DCI): m / z = 254 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.32 (s, 1H), 6.95 (s, 1H), 3.65-3.58 (m, 4H), 2.70 (quintet, 1H), 2.27 (t, 4H), 2.00-1.93 (m, 2H), 1.87-1.75 (m, 2H), 1.67-1.55 (m, 2H).

Step b): 4- (4-Cyclobutylpiperazin-1-yl) -6-hydrazinopyrimidine

To a solution of 1.9 g (7.5 mmol) of 4-6- (4-cyclobutylpiperazin-1-yl) pyrimidine in 28 ml of ethanol, 4.4 ml (4.5 g, 89.7) are added dropwise with stirring at room temperature. mmol) hydrazine hydrate. The reaction solution was stirred for 16 hours at 80 ° C. For processing, the solution was concentrated in vacuo, the residue was stirred several times in diethyl ether, the precipitated solid was filtered off and dried in vacuo. The residue was then purified by silica gel column chromatography (solvent: dichloromethane / methanol 10/2). Yield: 1.5 g (80% of theory. Prob.).

LC-MS (method 6): R _t = 1.36 min; MS (ESIpos): m / z = 249 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.92 (s, 1H), 7.63 (s, 1H), 5.90 (NH), 4.09 (s, NH2), 3.45 (t, 4H), 2.69 (quintet, 1H), 2.26 (t, 4H), 2.00-1.93 (m. 2H), 1.82-1.75 (m, 2H), 1.67-1.60 (m, 2H).

Example 10A

1- (6-Hydrazinylpyrimidin-4-yl) acetidin-3-ol

Step a): 1- (6-chloropyrimidin-4-yl) acetidin-3-ol

7.3 g (48.7 mmol) of 4,6-dichloropyrimidine in 140 ml are suspended and mixed with 47 ml of 1 N sodium hydroxide. 5.3 g (48.7 mmol) of 3-hydroxyacetidine are added and the reaction mixture is stirred for 3 days at 90 ° C. After cooling to room temperature, the reaction mixture is concentrated in vacuo and used without further purification.

LC-MS (method 5): R _t = 0.36 min; MS (ESIpos): m / z = 1.87 [M + H] ⁺ .

Step b): 1- (6-Hydrazinylpyrimidin-4-yl) acetidin-3-ol

To a solution of 10.4 g (55.8 mmol) of 1- (6-chloropyrimidin-4-yl) acetidin-3-ol in 100 ml of ethanol, 27.2 ml (27.9 g, 279.1 mmol) are added dropwise with stirring. ) hydrazine hydrate at room temperature. The reaction solution was stirred for 16 hours at 80 ° C. For processing it is concentrated in vacuo, the precipitate is filtered off and washed twice with ethanol (10 ml each). Yield: 2.0 g (19% of theory. Prob.).

LC-MS (method I): R _t = 2.06 min; MS (ESIpos): m / z = 194 [M + H] ⁺ .

Example 11A

4-chloro-6-hydrazinopyrimidine

To a solution of 20.0 g (134.3 mmol) of 4,6-dichloropyrimidine in 300 ml of ethanol, 11.8 ml (12.1 g, 241.6 mmol) of hydrazine hydrate are added dropwise with stirring at room temperature. During the addition of hydrazine hydrate, the solution becomes turbid, and ethanol (about 400 ml) is added to it. The reaction solution was stirred for 12 hours at room temperature. For processing, the precipitated solid is filtered off, the filter cake is washed twice with 150 ml of water and twice with 100 ml of diethyl ether, and the product is dried in vacuum. A crystalline fraction of the product is obtained from the condensed mother liquor. Yield: 16.8 g (87% of theory. Prob.).

LC-MS (method 1): R _t = 1.17 min; MS (ESIpos): m / z = 145 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.81 (s, 1H), 8.17 (br. S, 1H), 6.75 (s, 1H), 4.48 (br. S, 2H).

Example 12A

2- (6-Chloropyrimidin-4-yl) -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazol-3-one hydrochloride

10.0 g (47.7 mmol) of the compound of Example 8A and 8.3 g (57.1 mmol) of the compound of Example PA were added to 100 ml of ethanol and diluted with 1.5 ml (2.2 g, 19.0 mmol) ) trifluoroacetic acid. The solution is stirred for 12 hours with reflux. Then, a 4M solution of hydrogen chloride in dioxane was added in excess to the cooled reaction mixture, the mixture was stirred for about 1 hour, the precipitated crystals were filtered off, and the filter cake was washed with dioxane and ethanol. The resulting intermediate was dissolved in 150 ml of ethanol, diluted with 50 ml of a 25% methanol solution of sodium methylate, and the mixture was stirred for 2 hours at room temperature. Then the reaction mixture was acidified with 1 N hydrochloric acid to pH = 5, stirred for another 2 hours at room temperature, the residue was filtered off, the filter cake was washed with ethanol, and the product was dried in vacuo. Yield: 7.0 g (49% of theory. Prob.).

LC-MS (method 5): R _t = 1.20 min; MS (ESIpos): m / z = 264 [M + H] ⁺

Example 13A

2- (6-Chloropyrimidin-4-yl) -4- (1H-imidazol-1-yl) -1,2-dihydro-3H-pyrazol-3-one hydrochloride

10.0 g (47.8 mmol) of the compound of Example 5A and 8.3 g (57.3 mmol) of the compound of Example HA are introduced into 100 ml of ethanol and diluted with 1.5 ml (2.2 g, 19.0 mmol) ) trifluoroacetic acid. The solution is stirred for 12 hours with reflux. The precipitated crystals are filtered off, the filter cake is washed with ethanol, and the intermediate is dried overnight in vacuo. Then this product is turned into a suspension of 20 ml, diluted with 100 ml of a 4 M solution of hydrogen chloride in dioxane, and the mixture is stirred for 1 hour at room temperature. The solid was filtered off, the filter cake was washed with dioxane, ethyl acetate and diisopropyl ether, and the product was dried in vacuo. Yield: 4.6 g (32% of theory. Prob.).

HPLC (method 6): R _t = 2.81 min; MS (ESIpos): m / z = 263 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.46 (s, 1H), 8.96 (s, 1H), 8.56 (s, 1H), 8.51 (d, 1H), 8.07-8.04 (m, 1H), 7.85-7.82 (m, 1H).

Example 14A

4- (6-Hydrazinylpyrimidin-4-yl) -1,4-oxazepan

Step a): 4- (6-Chloropyrimidin-4-yl) -1,4-oxazepan

A mixture of 3.0 g (20.1 mmol) of 4,6-dichloropyrimidine, 2.8 g (20.1 mmol) of 1,4-oxazepane hydrochloride and 6.4 g (60.4 mmol) of sodium carbonate in 45 ml of water is stirred for 16 hours with reflux. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo to dryness. The product is obtained in the form of an oil. Yield: 3.9 g (86% of theory. Prob.).

LC-MS (method 4): R _t = 1.32 min; MS (ESIpos): m / z = 214 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.33 (s, 1H), 6.86 (s, 1H), 3.99-3.52 (m, 8H), 1.84 (m, 2H).

Step b): 4- (6-Hydrazinylpyrimidin-4-yl) -1,4-oxazepan

To a solution of 3.9 g (18.0 mmol) of 4- (6-chloropyrimidin-4-yl) -1,4-oxazepane in 25 ml of ethanol, 8.8 ml (9.0 g, 180.2 mmol) hydrazine hydrate at room temperature. After 16 hours of stirring at 80 ° C, the reaction solution was concentrated in vacuo. The residue was stirred in cold ethanol, the precipitated solid was filtered off, and the filter cake was washed with 25 ml of diethyl ether. The product is dried in vacuo. Yield: 1.4 g (36% of theory. Prob.).

HPLC (method 11): R _t = 2.48 min; MS (ESIpos): m / z = 210 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): 5 = 7.91 (s, 1H), 7.56 (br. S, 1H), 5.81 (s, 1H), 4.12 (br. S, 2H), 3.75- 3.55 (m, 8H); 1.85 (quintet, 2H).

Execution examples

Example 1

2- [6- (4-Cyclobutylpiperazin-1-yl) pyrimidin-4-yl] -4- (1H-imidazol-1-yl) -1,2-dihydro-3H-pyrazol-3-one

A mixture of 211 mg (1.0 mmol) of the compound of Example 5A and 250 mg (1.0 mmol) of the compound of Example 9A in 4 ml of ethyl acetate was diluted with 16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid and stirred 20 hours at 100 ° C. The reaction mixture was concentrated in vacuo, diluted again with the same amount of ethyl acetate and trifluoroacetic acid and stirred for another 20 hours at 100 ° C. The reaction mixture was cooled to room temperature, the precipitated solid was filtered off and washed with diethyl ether. The residue was first purified by column chromatography through silica gel (solvent: dichloromethane / methanol / ammonia 10/2 / 0.2), and then using preparative HPLC (RPlS column; solvent: acetonitrile / water gradient). Yield: 137 mg (36% of theory. Prob.).

HPLC (method 6): R _t = 2.73 min; MS (ESIpos): m / z = 367 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.40 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.50 (s, 1H) , 7.07 (s, 1H), 3.65-3.58 (m, 4H), 2.77 (quintet, 1H), 2.38-2.35 (m, 4H), 2.01-1.96 (m, 2H), 1.89-1.79 (m, 2H) . 1.67-1.62 (m, 2H).

Example 2

2- [6- (4-Cyclobutylpiperazin-1-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazol-3 -it

A mixture of 211 mg (1.0 mmol) of the compound of Example 8A and 250 mg (1.0 mmol) of the compound of Example 9A in 4 ml of ethyl acetate was diluted with 16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid and stirred 20 hours at 100 ° C. The reaction mixture is concentrated in vacuo, diluted again with the same amount of ethyl acetate and trifluoroacetic acid and stirred for 3 days at 100 ° C. The reaction mixture was cooled to room temperature, the precipitated solid was filtered off and washed with diethyl ether. The residue was suspended in 2 ml of water, dissolved by adding aqueous 1 N sodium hydroxide (pH = 9-10) and purified using preparative HPLC (RP18 column; solvent: acetonitrile / water gradient). Yield: 195 mg (51% of theory. Prob.).

HPLC (method 6): R _t = 2.90 min; MS (ESIpos): m / z = 368 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.41 (s, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H) , 3.70-3.65 (m, 4H), 3.03-2.97 (m, 1H), 2.60-2.57 (m, 4H), 2.06-2.02 (m, 2H), 1.98-1.90 (m, 2H), 1.70-1.64 ( m, 2H).

Example 3

1- {2- [6- (4-Cyclobutylpiperazin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazole-4-carbonitrile

A mixture of 236 mg (1.0 mmol) of the compound of Example 6A and 250 mg (1.0 mmol) of the compound of Example 9A in 4 ml of ethyl acetate is diluted with 16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid and stirred 20 hours at 100 ° C. The reaction mixture was concentrated in vacuo, diluted again with the same amount of ethyl acetate and trifluoroacetic acid and stirred for 3 days at 100 ° C. The reaction mixture was cooled to room temperature, the precipitated solid was filtered off and washed with diethyl ether. The residue was suspended in 2 ml of water, dissolved by adding aqueous 1 N sodium hydroxide (pH = 9-10) and purified using preparative HPLC (RP18 column; solvent: acetonitrile / water gradient). Yield: 219 mg (56% of theory. Prob.).

HPLC (method 6): R _t = 3.10 min; MS (ESIpos): m / z = 392 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.38 (d, 1H), 8.37 (d, 1H), 8.17 (d, 1H), 7.82 (s, 1H), 7.80 (s, 1H) , 3.68-3.62 (m, 4H), 3.38-3.30 (m, 4H), 2.96-2.91 (m, 1H), 2.06-2.00 (m, 2H), 1.95-1.85 (m, 2H), 1.70-1.63 ( m, 2H).

Example 4

1- {2- [6- (3-Hydroxyacetidin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazole-4-carbonitrile

A mixture of 700 mg (3.0 mmol) of the compound of Example 6A and 541 mg (3.0 mmol) of the compound of Example 10A in 10 ml of ethyl acetate was diluted with 46 μl (68 mg, 0.6 mmol) of trifluoroacetic acid and stirred 10 hours at 100 ° C. The reaction mixture was concentrated in vacuo, 5 ml of ethanol was dissolved, and the precipitate was filtered off. The solid was suspended in 10 ml of water and diluted to dissolve with 1 N sodium hydroxide (pH = 9). Then, pH = 7 was established with 1 N hydrochloric acid, the solution was concentrated to a volume of about 5 ml, and the precipitate formed was filtered off. The residue was washed with water and diisopropyl ether and chromatographed using preparative HPLC (method 8). Then the solid is suspended in 10 ml of water and diluted to dissolve with 1 N sodium hydroxide (pH = 9). Then, pH = 7 was established using 1 N hydrochloric acid, the solution was concentrated to a volume of about 2.5 ml, and the precipitate formed was filtered off. The filtrate was concentrated to a volume of about 2 ml and filtered again. Both residues were combined, washed with water and ethyl acetate, and dried in vacuo. . Yield: 78 mg (8% of theory. Prob.).

HPLC (method 6): R _t = 2.90 min; MS (ESIpos): m / z = 325 [M + H] ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.35 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.66 (s, 1H), 7.34 (s, 1H) , 5.80-5.75 (m, 1H), 4.63-4.58 (m, 1H), 4.24-4.20 (m, 2H), 3.75-3.73 (m, 2H).

Example 5

1- {6- [4- (1H-Imidazol-1-yl) -5-oxo-2,5-dihydro-1H-pyrazol-1-yl] pyrimidin-4-yl} acetidine-3-carboxylic acid

46 mg (0.3 mmol) of acetidine-3-carboxylic acid hydrochloride is added to a mixture of 1 ml of water and 0.3 ml of ethanol. 100 mg (0.3 mmol) of the compound of Example 13A was added and the mixture was stirred for 1 hour at 100 ° C. Then the reaction mixture was diluted with aqueous 1 N sodium hydroxide to pH = 7 and stirred for 16 hours at 100 ° C. Dilute again with 1 N sodium hydroxide to pH = 7 and exchange reaction for 1 hour at 150 ° C in a single-mode microwave oven {single mode-Mikrowelle (Emrys Optimizer)). The reaction mixture was concentrated in vacuo and purified by preparative HPLC (RPlS column; solvent: acetonitrile / water gradient). Yield: 23 mg (21% of theory. Prob.).

LC-MS (method 8): R _t = 0.86 min; MS (ESIpos): m / z = 328 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.41 (s, 1H), 7.79 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H) 6.89 (s, 1H); 4.09 (t, 2H); 3.99 (t, 2H).

Example 6

1- {6- [5-oxo-4- (177-1,2,3-triazol-1-yl) -2,5-dihydro-1H-pyrazol-1-yl] pyrimidin-4-yl} acetidine- 3-carboxylic acid

55 mg (0.4 mmol) of acetidine-3-carboxylic acid hydrochloride is added to 2 ml of water. 100 mg (0.3 mmol) of the compound of Example 12A was added and the mixture was diluted with aqueous 1 N sodium hydroxide to pH = 7. The solution is subjected to an exchange reaction in a single-mode microwave oven (Emrys Optimizer) for 1 hour at 150 ° C. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient). Yield: 15 mg (13% of theory. Prob.).

HPLC (method 6): R _t = 2.81 min; MS (ESIpos): m / z = 329 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.42 (s, 1H), 8.26 (s, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.34 (s, 1H), 4.05-3.96 (m, 2H and 2H), 3.13-3.07 (m, 1H).

Example 7

4- (1H-Imidazol-1-yl) -2- [6- (3-methylacetidin-1-yl) pyrimidin-4-yl] -1,2-dihydro-3H-pyrazol-3-one

43 mg (0.4 mmol) of 3-methylacetidine hydrochloride, 100 mg (0.3 mmol) of the compound of Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N- (propan-2-yl) propane The -2-amine is suspended in 2 ml of tetrahydrofuran and the mixture is subjected to an exchange reaction for 4.5 hours at 120 ° C. in a single-mode microwave oven (Emrys Optimizer). The reaction mixture was concentrated in vacuo, diluted with water with the addition of aqueous 1 N sodium hydroxide (to pH = 9-10) and purified by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient). Yield: 30 mg (30% of theory. Prob.).

HPLC (method b): Rt = 3.07 min; MS (ESIpos): m / z = 298 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.25 (s, 1H), 7.81 (s, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H) 6.88 (s, 1H), 4.10 (t, 2H), 3.54 (dd, 2H), 2.86-2.75 (m, 1H), 1.25 (d, 3H).

Example 8

2- [6- (3-Methylacetidin-1-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazol-3 -it

43 mg (0.4 mmol) of 3-methylacetidine hydrochloride, 100 mg (0.3 mmol) of the compound of Example 12A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N- (propan-2-yl) propane The -2-amine is slurried in 2 ml of tetrahydrofuran, and the mixture is subjected to an exchange reaction for 1.5 hours at 120 ° C. in a single-mode microwave (Emrys Optimizer). The reaction mixture was concentrated in vacuo, diluted with water with the addition of aqueous 1 N sodium hydroxide (pH = 9-10), and purified by preparative HPLC (KP3 column; solvent: acetonitrile / water gradient). Yield: 25 mg (25% of theory. Prob.).

HPLC (method 6): R _t = 3.00 min; MS (ESIpos): m / z = 299 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.41 (s, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.41 (s, 1H) 4.11 (t, 2H), 3.56 (dd, 2H), 2.86-2.78 (m, 1H), 1.25 (d, 3H).

Example 9

2- {6- [3- (Dimethylamino) acetidin-1-yl] pyrimidin-4-yl} -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H- pyrazole-Z-dihydrochloride

271 mg (1.5 mmol) of N, N-dimethylacetidin-3-amine dihydrochloride, 400 mg (1.5 mmol) of the compound of Example 12A and 847 mg (6.1 mmol) of potassium carbonate are suspended in 8 ml of N, N-dimethylformamide and the mixture was stirred for 16 hours at 100 ° C. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient with 0.1% trifluoroacetic acid). The following purification was carried out by preparative HPLC (RP18 column; solvent: acetonitrile / water gradient with 0.1% formic acid). The product fractions were diluted with 2 ml of 1 N hydrochloric acid and stirred for 1 hour at room temperature. The solid is filtered off and dried in vacuo. Yield: 62 mg (17% of theory. Prob.).

LC-MS (method 5): R _t = 0.19 min; MS (ESIpos): m / z = 328 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.42 (s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H) 4.02 (t, 2H), 3.76 (dd, 2H), 3.24-3.18 (m, 1H), 2.12 (s, 6H).

Example 10

2- [6- (4,4-difluoropiperidin-1-yl) pyrimidin-4-yl] -4- (1H-imidazol-1-yl) -1,2-dihydro-3H-pyrazol-3-one

100 mg (0.3 mmol) of the compound of Example 13A, 63 mg (0.4 mmol) of 4,4-difluoropiperidine hydrochloride and 116 μl (86 mg, 0.7 mmol) of N-ethyl-N- (propan-2 -yl) propanp2-amine is introduced into 2 ml of tetrahydrofuran, and the mixture is subjected to an exchange reaction for 2.5 hours at 120 ° C. in a single-mode microwave oven (Emrys Optimizer). After the mixture was concentrated in vacuo, the residue was diluted in acetonitrile and water and purified by preparative HPLC (RP18 column; solvent: acetonitrile / water gradient). Yield: 82 mg (71% of theory. Prob.).

HPLC (method 6): R _t = 3.37 min; MS (ESIpos): m / z = 348 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-dg): § = 8.49 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.22 (s, 1H), 3.80 (t, 4H), 2.06 (heptet, 4H).

Example 11

2- [6- (4,4-difluoropiperidin-1-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazole -3-he

250 mg (0.8 mmol) of the compound of Example 12A, 158 mg (1.0 mmol) of 4,4-difluoropiperidine hydrochloride and 435 μl (323 mg, 2.5 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is introduced into 5 ml of tetrahydrofuran, and the mixture is subjected to an exchange reaction for 30 minutes at 120 ° C in a single-mode microwave oven (Emrys Optimizer). After preliminary purification of the mixture by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient), the product was further purified by column chromatography through silica gel (solvent: dichlomethane / methanol, 10/1). Yield: 29 mg (10% of theory. Prob.). HPLC (method 6): R _t = 3.49 min; MS (ESIpos): m / z = 349 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.56 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.87 (s, 1H), 7.57 (s, 1H) 3.91-3.81 (m. 4H); 2.09 (heptet, 4H).

Example 12

1- {2- [6- (4,4-difluoropiperidin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazol-4 carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound of Example HA, 262 mg (1.7 mmol) of 4,4-difluorosheriding hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is stirred in 3 ml of water for 16 hours at 100 ° C. After adding 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 324 mg (1.4 mmol) of the compound of Example 6A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 111 mg (21% of theory. Prob.).

LC-MS (method 4): R _t = 1.69 min; MS (ESIpos): m / z = 373 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.55 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.22 (d, 1H), 7.60 (br. S, 1H), 3.84 (br. S, 4H), 2.09 (heptet, 4H).

Example 13

1- {2- [6- (4,4-difluoropiperidin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-1,2 , 3-triazole-4-carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound of Example HA, 262 mg (1.7 mmol) of 4,4-difluoropiperidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is stirred in 3 ml of water for 16 hours at 100 ° C. After adding 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 325 mg (1.4 mmol) of the compound of Example 7A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 34 mg (7% of theory. Prob.).

LC-MS (method 4): R _t = 1.77 min; MS (ESIpos): m / z = 374 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.24 (s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 7.54 (s, 1H), 3.90 (br s, 4H), 2.12 (heptet, 4H).

Example 14

2- [6- (3,3-difluoropyrrolidin-1-yl) pyrimidin-4-yl] -4- (1H-imidazol-1-yl) -1,2-dihydro-3H-pyrazol-3-one

100 mg (0.3 mmol) of the compound of Example 13A, 58 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 175 μl (130 mg, 1.0 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is introduced into 2 ml of tetrahydrofuran, and the mixture is subjected to an exchange reaction for 1 hour at 120 ° C in a single-mode microwave oven (Emrys Optimizer). After concentration in vacuo, the residue was diluted with acetonitrile and water and purified by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient). Yield: 111 mg (99% of theory. Prob.).

HPLC (method 6): R _t = 3.18 min; MS (ESIpos): m / z = 334 [M + H] ⁺ ;

¹ H-NMR (400 MHz, methanol-d ₄ ): δ = 8.41 (s, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.56 (s, 1H). 7.29 (s, 1H), 7.03 (s, 1H), 3.91 (t, 2H), 3.76 (t, 2H), 2.55 (heptet, 2H).

Example 15

2- [6- (3,3-difluoropyrrolidin-1-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazole -3-he

100 mg (0.8 mmol) of the compound of Example 12A, 57 mg (0.4 mmol) of 3,3-difluoropyrrolidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is introduced into 2 ml of tetrahydrofuran, and the mixture is subjected to an exchange reaction for 30 minutes at 120 ° C in a single-mode microwave oven (Emrys Optimizer). After concentration in vacuo, the residue was diluted with acetonitrile and water and purified by preparative HPLC (PpP18 column; solvent: acetonitrile / water gradient). Yield: 13 mg (12% of theory. Prob.).

HPLC (method 6): R _t = 3.33 min; MS (ESIpos): m / z-335 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.42 (s, 1H), 8.35 (s, 1H), 7.72-7.66 (m, 3H), 3.87 (t, 2H), 3.65 (t, 2H), 2.64-2.50 (m, partly with a signal from DMSO, 2H).

Example 16

1- {2- [6- (3,3-difluoropyrrolidin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazole-4 carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound of Example 11A, 238 mg (1.7 mmol) of 3,3-difluoropyrrolidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine in 3 ml of water is stirred for 16 hours at 100 ° C. After adding 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 324 mg (1.4 mmol) of the compound of Example 6A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The reaction mixture was mixed with 1 ml of 1 N hydrochloric acid. The resulting hydrochloride salt of the starting material is filtered off, washed with diethyl ether and dried. The intermediate product also contains the unreacted starting material (compound of Example HA). Therefore, the intermediate is subjected to an exchange reaction with 108 μl (80 mg, 0.6 mmol) of N-ethyl-N- (propan-2-yl) propan-2-amine, 10 mg (0.1 mmol) of 3,3-difluoropyrrolidine hydrochloride and 2 ml of water for 15 minutes at 170 ° C in a single-mode microwave (Emrys Optimizer). The reaction solution was purified by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient). Yield: 30 mg (6% of theory. Prob.).

LC-MS (method 4): R _t = 1.58 min; MS (ESIpos): m / z = 359 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): 8 = 8.55 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.21 (d, 1H), 7.26 (br. S, 1H), 3.99 (t, 2H), 3.75 (br. S, 2H), 2.66-2.54 (m, partially with the signal from DMSO, 2H).

Example 17

1- {2- [6- (3,3-difluoropyrrolidin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-1,2 3-triazole-4-carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound of Example 11A, 238 mg (1.7 mmol) of 3,3-difluoropyrrolidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine in 33 ml of water is stirred for 16 hours at 100 ° C. After adding 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 325 mg (1.4 mmol) of the compound of Example 7A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 137 mg (27% of theory. Prob.).

LC-MS (method 4): R _t = 1.66 min; MS (ESIpos): m / z = 360 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.25 (s, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 7.21 (br.s, 1H), 4.06 (t, 2H), 3.82 (br. S, 2H), 2.69-2.55 (m, partially with the signal from DMSO, 2H).

Example 18

2- [6- (3,3-difluoroacetidin-1-yl) pyrimidin-4-yl] -4- (1H-imidazol-1-yl) -1,2-dihydro-3H-pyrazol-3-one

100 mg (0.3 mmol) of the compound of Example 13A, 52 mg (0.4 mmol) of 3,3-difluoroacetidine hydrochloride and 175 μl (130 mg, 1.0 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is introduced into 2 ml of tetrahydrofuran, and the mixture is subjected to an exchange reaction for 3 hours at 120 ° C in a single-mode microwave oven (Emrys Optimizer). The precipitated solid is filtered off and the filtrate is concentrated in vacuo. The residue was diluted with acetonitrile and water and purified by preparative HPLC (RP18 column; solvent: acetonitrile / water gradient). Yield: 36 mg (32% of theory. Prob.).

HPLC (method 6): R _t = 3.00 min; MS (ESIpos): m / z = 320 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.42 (s, 1H), 8.16 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H) 7.07 (s, 1H); 4.49 (t, 4H).

Example 19

2- [6- (3,3-difluoroacetidin-1-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazole -3-he

100 mg (0.3 mmol) of the compound of Example 12A, 52 mg (0.4 mmol) of 3,3-difluoroacetidine hydrochloride and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is introduced into 2 ml of tetrahydrofuran, and the mixture is subjected to an exchange reaction for 30 minutes at 120 ° C in a single-mode microwave oven (Emrys Optimizer). After thickening in vacuo, the residue was diluted with acetonitrile and water and purified by preparative HPLC (RP18 column; solvent: acetonitrile / water gradient). Yield: 36 mg (34% of theory. Prob.).

HPLC (method 6): R _t = 3.20 min; MS (ESIpos): m / z = 321 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.42 (s, 1H), 8.39 (s, 1H), 7.71 (s, 2H), 7.62 (s, 1H), 4.46 (t, 4H) .

Example 20

1- {2- [6- (3,3-difluoroacetidin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazole-4 carbonitrile

A mixture of 120 mg (0.8 mmol) of the compound of Example 11A, 129 mg (1.0 mmol) of 3,3-difluoroacetidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine is stirred in 3 ml of water for 16 hours at 100 ° C.

After adding 32 μl (47 mg, 0.4 mmol) of trifluoroacetic acid and 194 mg (0.8 mmol) of the compound of Example 6A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 32 mg (11% of theory. Prob.).

LC-MS (method 4): R _t = 1.48 min; MS (ESIpos): m / z = 345 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.80-8.08 (m, 4H), 7.25 (s, 1H), 4.61 (br. S, 4H).

Example 21

1- {2- [6- (3,3-difluoroacetidin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-1,2 , 3-triazole-4-carbonitrile

A mixture of 120 mg (0.8 mmol) of the compound of Example 11A, 129 mg (1.0 mmol) of 3,3-difluoroacetidine hydrochloride and 174 μl (129 mg, 1.0 mmol) of N-ethyl-N- (propan-2 -yl) propan-2-amine in 3 ml of water is stirred for 16 hours at 100 ° C. After adding 32 μl (47 mg, 0.4 mmol) of trifluoroacetic acid and 194 mg (0.8 mmol) of the compound of Example 7A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 51 mg (18% of theory. Prob.).

LC-MS (method 4): R _t = 1.56 min; MS (ESIpos): m / z = 346 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.26 (s, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 7.18 (s, 1H), 4.69 (t, 4H) .

Example 22

4- (1H-Imidazol-1-yl) -2- [6- (1,4-oxazepan-4-yl) pyrimidin-4-yl] -1,2-dihydro-3H-pyrazol-3-one-hydrochloride

A mixture of 200 mg (1.0 mmol) of the compound of Example 5A, 200 mg (1.0 mmol) of the compound of Example 14A and 37 μl (54 mg, 0.5 mmol) of trifluoroacetic acid in 3 ml of water was stirred for 16 hours at 100 ° C. After preliminary purification by preparative HPLC (LR18 column; solvent: acetonitrile / water gradient), the intermediate was stirred with 1 ml of 1 N hydrochloric acid, filtered and washed with diethyl ether. The product is dried in vacuo. Yield: 21 mg (6% of theory. Prob.)

LC-MS (method 4): R _t = 0.95 min; MS (ESIpos): m / z = 364 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): 5 = 9.46 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.06 (t, 1H), 7.83 (t, 1H) 7.50-7.33 (m, 1H), 4.05 (br.s, 2H), 3.91-3.70 (m, 4H), 3.68 (t, 2H), 2.04-1.73 (m, 2H).

Example 23

2- [6- (1,4-Oxazepan-4-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazole -3-on-hydrochloride

A mixture of 400 mg (1.3 mmol) of the compound of Example 12A and 220 mg (1.6 mmol) of 1,4-oxazepane hydrochloride was exchanged in 4 ml of propan-2-ol for 30 minutes at 115 ° C in a single-mode microwave ovens (Emrys Optimizer). 232 μl (172 mg, 1.3 mmol) of N-ethyl-N- (propan-2-yl) propan-2-amine are added, and the reaction mixture is subjected to an exchange reaction for 20 minutes at 115 ° C. in a single-mode microwave ( Emrys Optimizer). After concentration in vacuo, the residue was diluted with acetonitrile / water / trifluoroacetic acid and treated with preparative HPLC (method 9). Obtained by separation by HPLC chromatography, the lyophilized trifluoroacetate salt is transferred into hydrochloride using 2 ml of 1 N hydrochloric acid. Yield: 7 mg (1% of theory. Prob.).

LC-MS (method 4): R _t = 1.20 min; MS (ESIpos): m / z = 329 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ-8.54 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.86 (d, 1H), 7.35 (br s, 1H), 4.14-3.69 (m, 6H), 3.67 (t, 2H), 2.03-1.77 (m, 2H).

Example 24

2- [6- (1,4-Oxazepan-4-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazole -3-he

A mixture of 500 mg (1.7 mmol) of the compound of Example 12A, 688 mg (5.0 mmol) of 1,4-oxazepane hydrochloride and 1.4 ml (1077 mg, 8.3 mmol) of N-ethyl-N- (propane The -2-yl) propan-2-amine is exchanged in 10 ml of tetrahydrofuran and ethanol (1/1) for 30 minutes at 140 ° C. in a single-mode microwave oven (Emrys Optimizer). After preliminary purification by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient), the intermediate was diluted with acetonitrile and trifluoroacetic acid and treated with preparative HPLC (method 10). In the obtained by separation by chromatography HPLC, lyophilized salt of trifluoroacetate using 1 N sodium hydroxide set pH = 7-8. The product was isolated by preparative HPLC (KP3 column; solvent: acetonitrile / water gradient). Yield: 176 mg (31% of theory. Prob.).

LC-MS (method 4): R _t = 1.19 min; MS (ESIpos): m / z = 329 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): 6 = 8.41 (d, 1H), 8.33 (d, 1H), 7.78 (br.s, 1H), 7.72-7.70 (m, 2H), 3.91- 3.65 (m, 6H), 3.62 (t, 2H), 1.95-1.83 (m, 2H).

Example 25

1- {2- [6- (1,4-Oxazepan-4-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazol-4 carbonitrile

A mixture of 200 mg (0.9 mmol) of the compound of Example 6A, 178 mg (0.9 mmol) of the compound of Example 14A and 33 μl (49 mg, 0.4 mmol) of trifluoroacetic acid in 3 ml of water was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 120 mg (40% of theory. Prob.).

HPLC (method 6): R _t = 3.27 min; MS (ESIpos): m / z = 353 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.52 (s, 1H), 8.42 (d, 1H), 8.25 (s, 1H), 8.19 (d, 1H). 7.39 (br. S, 1H), 4.14-3.70 (m, 6H), 3.66 (t, 2H), 2.05-1.68 (m, 2H).

Example 26

1- {2- [6- (1,4-Oxazepan-4-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-1,2 , 3-triazole-4-carbonitrile

A mixture of 200 mg (0.9 mmol) of the compound of Example 7A, 178 mg (0.9 mmol) of the compound of Example 14A and 33 μl (49 mg, 0.4 mmol) of trifluoroacetic acid in 3 ml of water was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 80 mg (27% of theory. Prob.).

LC-MS (method 4): R _t = 1.40 min; MS (ESIpos): m / z = 354 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.22 (s, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.45-7.26 (m, 1H), 4.06 (br. s, 2H), 3.92-3.71 (m, 4H), 3.68 (t, 2H), 2.06-1.74 (m, 2H).

Example 27

2- [6- (1,2-Oxazinan-2-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazole -3-he

A mixture of 200 mg (0.7 mmol) of the compound of Example 12A, 99 mg (0.8 mmol) of 1,2-oxazinane hydrochloride [Bhat et al., J. Chem. Soc. Perkin Trans. 2 2000, 7, 1435-1446] and 348 μl (258 mg, 2.0 mmol) of N-ethyl-N- (propan-2-yl) propan-2-amine are exchanged in 4 ml of tetrahydrofuran for 30 minutes at 140 ° C in a single-mode microwave (single mode-Mikrowelle (Emrys Optimizer)). After preliminary purification by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient), the intermediate was diluted with acetonitrile / water / methanol and treated with preparative HPLC (method 11). In the obtained by separation by chromatography HPLC, lyophilized salt of the formate with 1 N sodium hydroxide set pH = 7-8. The product was isolated by preparative HPLC (KP18 column; solvent: acetonitrile / water gradient). Yield: 23 mg (11% of theory. Prob.).

LC-MS (method 4): R _t = 1.38 min; MS (ESIpos): m / z = 315 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.58 (d, 1H), 8.42 (d, 1H), 8.40 (br. S, 1H), 7.88 (d, 1H), 7.66 (br. s, 1H), 4.09 (t, 2H), 3.98 (t, 2H), 1.86-1.68 (m, 4H).

Example 28

1- {2- [6- (1,2-Oxazinan-2-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazol-4 carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound of Example 11A, 205 mg (1.7 mmol) of 1,2-oxazinane hydrochloride [Bhat et al., J. Chem. Soc. Perkin Trans. 2 2000, 7, 1435-1446] and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N- (propan-2-yl) propan-2-amine in 3 ml of water are stirred for 1.5 hours at 100 ° C. After adding 59 μl (49 mg, 0.4 mmol) of trifluoroacetic acid and 324 mg (1.4 mmol) of the compound of Example 6A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 199 mg (39% theory. Prob.) LC-MS (method 5): R _t = 0.87 min; MS (ESIpos): m / z = 339 [M + H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d ₆ ): 8 = 8.57 (d, 1H), 8.45 (d, 1H), 8.40 (br. S, 1H), 8.23 (d, 1H), 7.70 (br. s, 1H), 4.07 (t, 2H), 3.96 (t, 2H), 1.85-1.65 (m, 4H).

Example 29

1- {2- [6- (1,2-Oxazinan-2-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-1,2 , 3-triazole-4-carbonitrile

A mixture of 200 mg (1.4 mmol) of the compound of Example HA, 205 mg (1.7 mmol) of 1,2-oxazinane hydrochloride [Bhat et al., J. Chem. Soc. Perkin Trans. 2 2000, 7, 1435-1446] and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N- (propan-2-yl) propan-2-amine in 3 ml of water are stirred for 1.5 hours at 100 ° C. After adding 59 μl (49 mg, 0.4 mmol) of trifluoroacetic acid and 325 mg (1.4 mmol) of the compound of Example 7A, the resulting reaction mixture was stirred for 16 hours at 100 ° C. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried in vacuo. Yield: 122 mg (24% of theory. Prob.).

LC-MS (method 4): R _t = 1.66 min; MS (ESIpos): m / z = 340 [M + H: G;

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 9.28 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.60 (br.s, 1H), 4.12 (t, 2H ), 4.03 (t, 2H), 1.88-1.70 (m, 4H).

B. Assessment of pharmacological efficacy

The pharmacological properties of the compounds according to the invention can be shown in the following tests:

Abbreviations:

DMEM Dulbecco's Modified Eagle

FCS remaining calf serum

TMB 3.3 ', 5.5'-tetramethylbenzidine

Iris Tris (hydroxymethyl) -aminomethane

1. In vitro tests to determine the activity and selectivity of inhibitors of H1P-prolyl-4-hydroxide basics

1.a) Inhibition of HIF-prolyl hydroxylase activity:

Hydroxylated HIF is especially attached to the Hippel-Lindau protein complex - elongin B - elongin C (VBC complex). Such an interaction occurs only if HIF is hydroxylated in the preserved residue shed. This is the basis for the biochemical determination of the activity of HIF-prolyl hydroxylase. The test is carried out according to the method described in the article [Oehme F., Jonghaus W., Narouz-Ott L., Huetter J., Flamme I., Anal. Biochem. 330 (1), 74-80 (2004)]:

A clear, 96-well NeutrAvidin HBC coated Microtiter plate (Pierce) was incubated for 30 minutes with a casein blocker. The plate is then washed three times with 200 μl washing buffer (50 mM Tris, pH 7.5, 100 mM Nad, 10% (v / v) blocker-casein, 0.05% (v / v) Tween 20) per well. Biotin-DLDLEMLAPYIPMDDDFQL peptide (Eurogentec, 4102 Seraing, Belgium) was added at a concentration of 400 nM per 100 μl of washing buffer solution. This peptide serves as a nutrient medium for prolyl hydroxylation and is bound to a microtiter plate. After 60 minutes of incubation, the plate is washed three times with washing buffer, 30 minutes the biotin is incubated in a casein blocker, and then washed three times with washing buffer.

To perform the prolyl hydroxylase reaction, the peptide-bound nutrient medium bound to the plate is incubated for 1-60 minutes with a cell lysate containing prolyl hydroxylase. The reaction is carried out in 100 μl of reaction buffer solution (20 mm Tris, pH 7.5, 5 mm KCl, 1.5 mm MgCl ₂ , 1 μm-1 mm 2-oxoglutarate, 10 μm FeSO ₄ , 2 mm ascorbate) at room temperature. In addition to the inhibitor intended for testing, the reaction mixture contains prolyl hydroxylase in various concentrations. A test substance is preferred, but only at concentrations between 1 nM and 100 μM. By washing the tablet three times with washing buffer, the reaction is stopped.

To quantify prolyl hydroxylation, a compound protein is added that contains both thioredoxin from E. coli (from the microflora of Escherichia coli) and the VBC complex in 80 μl of binding buffer solution (50 mM Tris, pH 7.5, 120 mM NaCl). After 15 minutes, 10 μl of rabbit polyclonal anti-thioredoxin antibody solution was added to the binder buffer. After 30 minutes of incubation at room temperature, the plate was washed three times with washing buffer to remove unbound antibodies and the VBC complex. To determine the amount of bound VBC complex, incubation is performed for 15 minutes with TMB. The reaction to be colored is stopped by adding 100 μl of 1M sulfuric acid. The amount of bound VBC complex is determined by measuring the optical density at a wavelength of 450 nm. It is proportional to the amount of hydroxylated shed in the peptide nutrient medium.

Alternatively, an europium-linked VBC complex (Perkin Elmer) can be used to indicate prolyl hydroxylation. In this case, the amount of bound VBC complex is determined by fluorescence time. In addition, it is possible to use a VBC complex labeled with radioactive [ ³⁵ S] methionine. For this, a VBC complex with a radioactive label can be made in the laboratory by transcription-translation into a reticulocyte lysate.

Performance examples inhibit the activity of HIF-prolyl hydroxylase in this test with an IC _{50 of the} order of <30 μM. The following table 1 shows the typical indicators 1C5o for examples of execution.

Table 1 Example No. IC ₅₀ [nM] Example No. IC ₅₀ [nM] 2 880 21 70 5 540 25 180 9 760 26 380 17 130 29th 170 twenty 90

1.b) Cell, functional test in vitro:

The effectiveness of the compounds according to the invention is quantified using a recombinant cell line. Cells were originally obtained from human lung cancer cell lines (A549, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell line is stably transported by a vector that contains the reporter Photinus pyralis luciferase gene (hereinafter referred to as luciferase) under the control of an artificial mini-motor. The mini-motor consists of two elements that are sensitive to hypoxia against the sequence of the TATA block [Oehme F., Ellinghaus P., Kolkhof P., Smith T.J., Ramakrishnan S., Htitter J., Schramm M., Flamme I., Biochem. Biophys. Res. Commun. 296 (2), 343-9 (2002)]. When exposed to hypoxia (for example, culturing in the presence of 1% oxygen for 24 hours) or when exposed to non-selective oxygenase inhibitors (for example, desferroxamine at a concentration of 100 μM, cobalt chloride at a concentration of 100 μM or iV-oxalyl glycine diethyl ether at a concentration of 1 mm) the cell line produces luciferase, which can be detected and quantified using suitable bioluminescence reagents (e.g., Steady-Glo® Luciferase Assay System, Promega Corporation, Madison, Wisconsin 53711, USA) and by luminometer.

Test run: Cells were introduced the day before the test into accurately measured growth media (DMEM, 10% FCS, 2 tM glutamine) in a microtiter plate with 384 or 1536 wells and placed in a cell incubator (96% air humidity, 5% v / v CO ₂ , 37 ° C). On the day of the test, test substances in step concentrations are added to the nutrient medium. The test substance is not added to the consoles serving as a negative control to the cells. As a positive control for determining the sensitivity of cells to inhibitors, for example, desferroxamine at a final concentration of 100 μM is added. 6-24 hours after applying the test substances to the wells of a microtiter plate, the resulting light signal is measured in a luminometer. From the measured values establish the ratio of the dose of action, which serves as the basis for determining the half-maximum concentration of action (denoted as EC ₅₀ ).

1.c) Cellular, functional in vitro test for changing gene expression:

In order to investigate the change in the expression of specific mRNAs in human cell lines after treatment with test substances, the following cell lines were cultured on 6 or 24 well plates:

human hepatoma cells (HUH, JCRB Cell Bank, Japan), human embryonic renal fibroplast (HEK / 293, ATCC, Manassas, Virginia 20108, USA), human neck cancer cells (HeLa, ATCC, Manassas, Virginia 20108, USA) , human umbilical cord venous endothelial cells (HUVEC, Cambrex, East Rutherford, New Jersey 07073, USA). 24 hours after the addition of the test substances, the cells are washed with physiological phosphate saline and the total RNA is obtained from them (for example, Trizol®-Reagenz, Invitrogen GmbH, 76131 Karlsruhe, Germany).

For a routine analytical experiment, every 1 μg of total RNA thus obtained is digested with Dnase 1, and a suitable transcriptase reverse reaction (ImProm-II Reverse Transcription System, Promega Corporation, Madison, WI 53711, USA) is converted to additional DNA (cDNA). 2.5% of the cDNA composition thus obtained is used for the polymerase chain reaction. The expression level of the studied mRNA genes is determined using a quantitative analysis of the polymerase chain reaction in real time [TaqMan-PCR; Heid C. A., Stevens J., Livak K.J., Williams P.M., Genome Res. 6 (10), 986-94 (1996)] using an ABI Prism 7700 sequential indicator (Applied Biosystems, Inc.). The seed-probe combinations used for this are generated by Primer Express 1.5 (Applied Biosystems, hie.). In particular, mRNAs of erythropoietin, carbonic anhydrase IX, lactate dehydrogenase A and vascular endothelial cell growth factor are examined.

Substances according to the present invention lead to a significant, dose-dependent increase in mRNA of hypoxia-induced genes in cells of human origin.

2. In vivo tests for evidence of action in the cardiovascular system

2.a) T vivo test for changing gene expression:

Mice or rats are administered test compounds dissolved in appropriate solvents orally or through a gastric tube, intraperitoneally or intravenously. Typical doses are 0.1, 0.5, 1.5, 10, 20, 50, 100 and 300 mg of substance per kg of body weight and intake. Control animals receive only solvent. 4, 8, or 24 hours after ingestion of the test substance, the animals were killed with an overdose of isoflurane followed by a fracture of the cervical spine, and organs intended for examination were removed. Organ fragments were instantly frozen in liquid nitrogen. From the organ fragments, the total RNA obtained was as described in paragraph B.I. a) is converted to cDNA. The expression level of the studied mRNA genes is determined using a quantitative analysis of the polymerase chain reaction in real time [TaqMan-PCR; Heid C.A., Stevens J., Livak K.J., Williams P.M., Genome Res. 6 (10), 986-94 (1996)] using an ABI Prism 7700 sequential indicator (Applied Biosystems, Inc.).

Substances according to the present invention after oral or parenteral administration lead to a significant, dose-dependent increase in erythropoietin mRNA in the kidney compared with control samples receiving placebo.

2.b) Determination of serum erythropoietin level:

The test substance is administered to mice or rats in an appropriate solvent either intraperitoneally or orally once or twice daily. Typical doses are 0.1, 0.5, 1, 5, 10, 20, 50, 100 and 300 mg of substance per kg of body weight and intake. Control animals receive only solvent. Before taking and four hours after the last injection of the drug in animals under short-term anesthesia, 50 μl of blood is taken from the retrobrbital venous plexus or from the tail vein. Blood coagulation is prevented by the addition of lithium heparin. By centrifugation, blood plasma is obtained. In the blood plasma, the erythropoietin content is determined using an Erythropoetin-ELISA (Quantikine® mouse Epo Immunoassay, R&D Systems, Inc., Minneapolis, USA) in accordance with the manufacturer's instructions. The measured values are converted to PG / ml based on the control measurement of erythropoietin in the mouse.

Substances according to the present invention after oral or parenteral administration lead to a significant, dose-dependent increase in erythropoietin compared with the initial indicator and with control samples receiving placebo.

2.c) Determination of the cellular composition of peripheral blood:

The test substance is administered to mice or rats in an appropriate solvent either intraperitoneally or orally once or twice for several days. Typical doses are, for example, 0.1, 0.5, 1.5, 10, 20, 50, 100 and 300 mg of substance per kg of body weight and intake. Control animals receive only solvent. At the end of the test, animals under short-term anesthesia take blood from the venous plexus of the corner of the palpebral fissure or from the caudal vein, and blood clotting is prevented by the addition of sodium citrate. In a suitable electronic measuring device, the concentration of red blood cells, white blood cells and platelets is determined in a blood sample. The concentration of eticulocytes is determined by blood smears, which are stained with an appropriate staining solution (CABE Labortechnik, Numbrecht) by viewing through a microscope each 1000 red blood cells. To determine the hematocrit, blood from the retroorbital plexus of the veins is taken using a hematocrit capillary, and the hematocrit value is read manually after processing the capillary in a suitable centrifuge.

Substances according to the present invention after oral or parenteral administration lead to a significant, dose-dependent increase in hematocrit, the number of red blood cells and white blood cells compared with the initial indicator and with control samples receiving placebo.

3. Determination of solubility

Preparation of stock solution ('primary solution):

At least 1.5 mg of the test substance is accurately weighed in a Wide Mouth 10 mm Screw V-Vial (Glastechnik Grafenroda GmbH, Art.-Nr. 8004-WM-H / V15 μm) with a suitable screw cap and baffle, the substance is diluted with DMSO to a concentration of 50 mg / ml and stir for 30 minutes using a vortex mixer.

Production of calibration solutions:

The required dosage steps are carried out on a Deep Well Plate (DWP) plate with 96 wells of 1.2 ml using fluid handling robots. The solvent used is a mixture of acetonitrile and water 8: 2.

Preparation of the initial solution for calibration solutions (concentrated solution): 10 μl of the primary solution was diluted with 833 μl of a mixture of solutions (concentration = 600 μg / ml) and the mixture was homogenized. Each test substance is diluted to a concentration of 1: 100 in separate DWP plates and homogenized again.

Calibration solution 5 (600 ng / ml): 30 μl of the concentrated solution is diluted with 270 μl of the mixture of solutions and homogenized.

Calibration solution 4 (60 ng / ml): 30 μl of calibration solution 5 is diluted with 270 μl of a mixture of solutions and homogenized.

Calibration solution 3 (12 ng / ml): 100 μl of calibration solution 4 is diluted with 400 μl of a mixture of solutions and homogenized.

Calibration solution 2 (1.2 ng / ml): 30 μl of calibration solution 3 is diluted with 270 μl of a mixture of solutions and homogenized.

Calibration solution 1 (0.6 ng / ml): 150 μl of calibration solution 2 is diluted with 150 μl of a mixture of solutions and homogenized.

Production of test solutions:

The necessary dosage steps are carried out in a DWP plate with 96 wells of 1.2 ml using fluid handling robots. 10.1 μl of the concentrated solution was diluted with 1000 μl of PBS buffer solution pH 6.5. (PBS buffer pH 6.5: 61.86 g sodium chloride, 39.54 g sodium dihydrogen phosphate and 83.35 g 1 N sodium hydroxide are weighed in a 1 liter volumetric flask, supplemented with water, and the mixture is stirred for about 1 hour. 500 ml of this solution is poured into a 5-liter volumetric flask and refilled with water. Using pH 1N, pH 6.5 is adjusted.)

Performance:

The necessary dosage steps are carried out in a DWP plate with 96 wells of 1.2 ml using fluid handling robots. The test solutions thus prepared are shaken for 24 hours at 1400 rpm using a thermostatic vortex mixer at 20 ° C. 180 μl of samples are taken from these solutions and placed in Beckman polyalomeric centrifuge tubes. These solutions are centrifuged for 1 hour with a force of 223,000 × g. 100 μl of the liquid fraction is taken from each test solution, which is diluted with PBS 6.5 buffer solution at a concentration of 1:10 and 1: 1000.

Analysis Method:

Sample analysis is performed using HPLC / MS-MS. Quantification is obtained from the five-point calibration curve of the test compound. Solubility is expressed in mg / L. Analysis sequence: 1) control sample (solvent mixture); 2) a calibration solution of 0.6 ng / ml; 3) a calibration solution of 1.2 ng / ml; 4) calibration solution 12 ng / ml; 5) calibration solution 60 ng / ml; 6) calibration solution 600 ng / ml; 7) control sample (mixture of solutions); 8) test solution 1: 1000; 7) test solution 1:10.

HPLC / MS-MS Method

HPLC: Agilent 1100, four-component pump (G1311A), STS HTS PAL automatic sampler, degasser (G1322A) and column thermostat (G1316A); column: Oasis HLB 20 mm × 2.1 mm, 25 microns; temperature: 40 ° C; solvent A: water + 0.5 ml of formic acid / l; solvent B: acetonitrile + 0.5 ml of formic acid / l; flow rate: 2.5 ml / min; stop time 1.5 min; gradient: 0 min 95% A, 5% B; change: 0-0.5 min 5% A, 95% B; 0.5-0.84 min 5% A, 95% B; change: 0.84-0.85 min 95% A, 5% B; 0.85-1.5 min 95% A, 5% B.

MS / MS: WATERS Quattro Micro Tandem MS / MS; Z-Spray API-Interface; HPLC-MS input divider 1:20; measurement in ESI mode.

C. Performance examples for pharmaceutical formulations

Compounds according to the invention can be converted into drugs as follows:

Pills:

Structure:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn cochmal (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigsgafen, Germany) and 2 mg of magnesium stearate.

The weight of the tablet is 212 mg. The diameter is 8 mm, the radius of convexity is 12 mm.

Manufacture:

A mixture of a compound according to the invention, lactose and starch with a 5% solution (w / w) PVP is granulated in water. After drying, the granular product is mixed for 5 minutes with magnesium stearate. This mixture is pressed with a standard tablet press (tablet format see above). A reference value for pressing is a press force of 15 kN.

Suspensions for oral administration:

Structure:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, PA, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of an oral suspension.

Manufacture:

Rodigel is converted into a suspension in ethanol, a compound according to the invention is added to the suspension. When stirring, add water. Stirring is continued for about 6 hours until the final swelling of the rodigel.

Solution for oral administration:

Structure:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention corresponds to 20 g of an oral solution.

Manufacture:

The compound according to the invention, when stirred in a mixture of polyethylene glycol and polysorbate, is converted into a suspension. The mixing process is continued until the compound according to the invention is completely dissolved.

Solution for intravenous infusion:

A compound according to the invention with a concentration below saturated solubility is dissolved in a physiologically acceptable solvent (for example, an isotonic sodium chloride solution, 5% glucose solution and / or 30% PEG 400 solution). The solution is filtered under sterile conditions and poured into sterile and pyrogen-free containers for injection.

Claims (16)

1. The compound of the formula

wherein
X is N or CH,
R ¹ means hydrogen or cyano,
R ² means a saturated 4-7 membered heterocyclyl radical linked through a nitrogen atom which contains from 1 to 2 heteroatoms selected from N and O,
moreover, the heterocyclyl residue may be substituted by one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl,
or
moreover, the heterocyclyl residue is substituted by 1-4 substituents fluorine, or one of its pharmaceutically acceptable salts. 2. The compound according to claim 1, characterized in that X means N or CH,
R ¹ means hydrogen or cyano,
R ² means a saturated 4-7 membered heterocyclyl radical linked through a nitrogen atom which contains from 1 to 2 heteroatoms selected from N or O, the heterocyclyl radical being substituted by 1-4 fluorine substituents,
or
R ² means piperazin-1-yl,
wherein piperazin-1-yl is substituted with one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl,
wherein piperazin-1-yl is substituted with one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl,
or
R ² means azetidin-1-yl,
wherein azetidin-1-yl is substituted with one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl,
or one of its pharmaceutically acceptable salts. 3. The compound according to claim 1, characterized in that
X is N or CH,
R ¹ means hydrogen or cyano,
R ² means azetidin-1-yl, pyrrolin-1-yl or piperidin-1-yl,
moreover, azetidin-1-yl, pyrrolin-1-yl and piperidin-1-yl are substituted with 1-4 fluorine substituents,
or
R ² means piperazin-1-yl,
wherein piperazin-1-yl in the 4th position is substituted with one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl,
or one of its pharmaceutically acceptable salts. 4. The compound according to claim 1, characterized in that
X is N or CH,
R ¹ means hydrogen or cyano,
R ² means piperazin-1-yl,
wherein piperazin-1-yl is substituted with one substituent, wherein the substituent is selected from the group consisting of C ₃ -C ₆ cycloalkyl,
or one of its pharmaceutically acceptable salts. 5. The compound according to claim 4, characterized in that
X is N or CH,
R ¹ means hydrogen or cyano,
R ² means piperazin-1-yl,
wherein piperazin-1-yl in the 4th position is substituted with one substituent, wherein the substituent is selected from the group consisting of C ₃ -C ₆ cycloalkyl,
or one of its pharmaceutically acceptable salts. 6. The compound according to claim 1, characterized in that
X is N or CH,
R ¹ means hydrogen or cyano,
R ² means azetidin-1-yl,
wherein azetidin-1-yl is substituted with one substituent selected from the group consisting of C ₃ -C ₆ cycloalkyl,
or one of its pharmaceutically acceptable salts. 7. The compound according to claim 1, characterized in that
R ² means 4-cyclobutyl-piperazin-1-yl. 8. 1- {2- [6- (4-Cyclobutylpiperazin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazole-4 β-carbonitrile according to claim 1, having the following formula

and its pharmaceutically acceptable salts. 9. 1- {2- [6- (4-Cyclobutylpiperazin-1-yl) pyrimidin-4-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} -1H-imidazole-4 β-carbonitrile according to claim 1, having the following formula

10. 2- [6- (4-Cyclobutylpiperazin-1-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-1H-pyrazole -3-he according to claim 1 of the following formula

or one of its pharmaceutically acceptable salts 11. 2- [6- (4-Cyclobutylpiperazin-1-yl) pyrimidin-4-yl] -4- (1H-1,2,3-triazol-1-yl) -1,2-dihydro-1H-pyrazole -3-he according to claim 10 of the following formula:

12. The compound of formula (I)

in which the residues X, R ¹ and R ² have the meanings indicated in one of claims 1 to 11, and which possesses the properties of selective HIF-prolyl-4-hydroxylase inhibitors for the treatment and / or prophylaxis of diseases mediated by the activity of HIF-prolyl-4 -hydroxylases. 13. The compound of formula (I)

in which the residues X, R ¹ and R ² have the meanings indicated in one of claims 1 to 11, for the manufacture of a medicament suitable for use in a method for the treatment and / or prophylaxis of cardiovascular diseases, heart failure, anemia, chronic kidney diseases and renal failure. 14. The method of obtaining the compounds of formula (I) or one of its pharmaceutically acceptable salts according to claim 1, characterized in that the compound of the formula

in which X, Z ¹ and R ¹ have the meanings indicated in claim 1, with a compound of the formula

wherein
Z ² means methyl or ethyl,
condensed into a compound of the formula

in which X, Z ¹ and R ¹ have the meanings indicated in claim 1,
and then in the presence of one of the acids is reacted with a compound of formula (III)

in which R ² has the meaning specified in claim 1,
and the compound thus obtained under these conditions, the reaction of the interaction of the compounds of formula (VII) with the compound of the formula (III) or under the influence of a base is converted into a cyclic compound of the formula (I),
and the compound of formula (I), if necessary, is converted into one of its salts using the appropriate (i) solvent and / or (ii) base or acid. 15. A drug having the properties of selective inhibitors of HIF-prolyl-4-hydroxylase and containing the compound according to one of claims 1 to 11 in an effective amount in combination with an inert, non-toxic, pharmaceutically acceptable excipient. 16. The drug according to clause 15 for the treatment and / or prevention of cardiovascular disease, heart failure, anemia, chronic kidney disease and renal failure.